Peptide synthesis

From Wikipedia, the free encyclopedia

 

Coupling of two amino acids in solution. The unprotected amine of one reacts with the unprotected carboxylic acid group of the other to form a peptide bond. The second reactive group (amine/acid) in each of the starting materials bears a protecting group.

In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl group of one amino acid to the amino group of another. Protecting group strategies are usually necessary to prevent undesirable side reactions with the various amino acid side chains. Chemical peptide synthesis most commonly starts at the carboxyl end of the peptide (C-terminus), and proceeds toward the amino-terminus (N-terminus). Protein biosynthesis (long peptides) in living organisms occurs in the opposite direction.

The chemical synthesis of peptides can be carried out using classical solution-phase techniques, although these have been replaced in most research and development settings by solid-phase methods (see below). Solution-phase synthesis retains its usefulness in large-scale production of peptides for industrial purposes however.

Chemical synthesis facilitates the production of peptides which are difficult to express in bacteria, the incorporation of unnatural amino acids, peptide/protein backbone modification, and the synthesis of D-proteins, which consist of D-amino acids.

Solid-phase synthesis

Solid-phase synthesis of a dipeptide using an (amine-functionalized) amide resin. The N-terminal protecting group (PG) can be Fmoc or Boc, depending on the protecting group scheme used (see below). The amino acid side chains (R₁, R₂ etc.) are orthogonally protected (not shown).

The established method for the production of synthetic peptides in the lab is known as solid-phase peptide synthesis (SPPS). Pioneered by Robert Bruce Merrifield, SPPS allows the rapid assembly of a peptide chain through successive reactions of amino acid derivatives on an insoluble porous support.

The solid support consists of small, polymeric resin beads functionalized with reactive groups (such as amine or hydroxyl groups) that link to the nascent peptide chain. Since the peptide remains covalently attached to the support throughout the synthesis, excess reagents and side products can be removed by washing and filtration. This approach circumvents the comparatively time-consuming isolation of the product peptide from solution after each reaction step, which would be required when using conventional solution-phase synthesis.

Each amino acid to be coupled to the peptide chain N-terminus must be protected on its N-terminus and side chain using appropriate protecting groups such as Boc (acid-labile) or Fmoc (base-labile), depending on the side chain and the protection strategy used (see below).

The general SPPS procedure is one of repeated cycles of alternate N-terminal deprotection and coupling reactions. The resin can be washed between each steps. First an amino acid is coupled to the resin. Subsequently, the amine is deprotected, and then coupled with the free acid of the second amino acid. This cycle repeats until the desired sequence has been synthesized. SPPS cycles may also include capping steps which block the ends of unreacted amino acids from reacting. At the end of the synthesis, the crude peptide is cleaved from the solid support while simultaneously removing all protecting groups using a reagent strong acids like trifluoroacetic acid or a nucleophile. The crude peptide can be precipitated from a non-polar solvent like diethyl ether in order to remove organic soluble by products. The crude peptide can be purified using reversed-phase HPLC. The purification process, especially of longer peptides can be challenging, because small amounts of several byproducts, which are very similar to the product, have to be removed. For this reason so-called continuous chromatography processes such as MCSGP are increasingly being used in commercial settings to maximize the yield without sacrificing on purity levels.

SPPS is limited by reaction yields, and typically peptides and proteins in the range of 70 amino acids are pushing the limits of synthetic accessibility. Synthetic difficulty also is sequence dependent; typically aggregation-prone sequences such as amyloids are difficult to make. Longer lengths can be accessed by using ligation approaches such as native chemical ligation, where two shorter fully deprotected synthetic peptides can be joined together in solution.

Peptide coupling reagents

An important feature that has enabled the broad application of SPPS is the generation of extremely high yields in the coupling step. Highly efficient amide bond-formation conditions are required. The minimization of amino acid racemization during coupling is also of vital importance to avoid epimerization in the final peptide product.

Amide bond formation between an amine and carboxylic acid is slow, and as such usually requires 'coupling reagents' or 'activators'. Activation of the carboxyl group generally involves the formation of an 'active ester' in situ. A selection of peptide coupling reagents are described below.

Carbodiimides

Amide bond formation using DIC/HOBt.

 

Carbodiimides such as dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC) are frequently used for amide bond formation. The reaction proceeds via the formation of a highly reactive O-acylisourea. This reactive intermediate is attacked by the peptide N-terminal amine, forming a peptide bond. Formation of the O-acylisourea proceeds fastest in non-polar solvents such as dichloromethane.

DIC is particularly useful for SPPS since as a liquid it is easily dispensed, and the urea byproduct (N,N'-Diisopropylcarbodiimide is easily washed away. Conversely, the related carbodiimide 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) is often used for solution-phase peptide couplings as its urea byproduct can be removed by washing during aqueous work-up.

HOBt

 

HOAt

 

Neighbouring group effect of HOAt

Carbodiimide activation opens the possibility for racemization of the activated amino acid. Racemization can be circumvented with 'racemization suppressing' additives such as the triazoles 1-hydroxy-benzotriazole (HOBt), and 1-hydroxy-7-aza-benzotriazole (HOAt). These reagents attack the O-acylisourea intermediate to form an active ester, which subsequently reacts with the peptide to form the desired peptide bond. Ethyl cyanohydroxyiminoacetate (Oxyma), an additive for carbodiimide coupling, acts as an alternative to HOAt.

Aminium/uronium and phosphonium salts

Uronium-based peptide coupling reagents

Some coupling reagents omit the carbodiimide completely and incorporate the HOAt/HOBt moiety as an aminium/uronium or phosphonium salt of a non-nucleophilic anion (tetrafluoroborate or hexafluorophosphate). Examples of aminium/uronium reagents include HATU (HOAt), HBTU/TBTU (HOBt) and HCTU (6-ClHOBt). HBTU and TBTU differ only in the choice of anion. Phosphonium reagents include PyBOP (HOBt) and PyAOP (HOAt).

These reagents form the same active ester species as the carbodiimide activation conditions, but differ in the rate of the initial activation step, which is determined by nature of the carbon skeleton of the coupling reagent. Furthermore, aminium/uronium reagents are capable of reacting with the peptide N-terminus to form an inactive guanidino by-product, whereas as phosphonium reagents are not.

Solid supports

Cross-linked polystyrene is the most common solid support used in SPPS.

Solid supports for peptide synthesis are selected for physically stability, to permit the rapid filtration of liquids. Suitable supports are inert to reagents and solvents used during SPPS, although they must swell in the solvents used to allow for penetration of the reagents, and allow for the attachment of the first amino acid.

Three primary types of solid supports are: gel-type supports, surface-type supports, and composites. Improvements to solid supports used for peptide synthesis enhance their ability to withstand the repeated use of TFA during the deprotection step of SPPS. Two primary resins are used, based on whether a C-terminal carboxylic acid or amide is desired. The Wang resin was, as of 1996, the most commonly used resin for peptides with C-terminal carboxylic acids.

Protecting groups schemes

As described above, the use of N-terminal and side chain protecting groups is essential during peptide synthesis to avoid undesirable side reactions, such as self-coupling of the activated amino acid leading to (polymerization). This would compete with the intended peptide coupling reaction, resulting in low yield or even complete failure to synthesize the desired peptide.

Two principle orthogonal protecting group schemes exist for use in solid-phase peptide synthesis: so-called Boc/Bzl and Fmoc/tBu approaches. The Boc/Bzl strategy utilizes TFA-labile N-terminal Boc protection alongside side chain protection that is removed using anhydrous hydrogen fluoride during the final cleavage step (with simultaneous cleavage of the peptide from the solid support). Fmoc/tBu SPPS uses base-labile Fmoc N-terminal protection, with side chain protection and a resin linkage that are acid-labile (final acidic cleavage is carried out via TFA treatment).

Both approaches, including the advantages and disadvantages of each, are outlined in more detail below.

Boc/Bzl SPPS

Cleavage of the Boc group

The original method for peptide synthesis relied on tert-butyloxycarbonyl (or more simply 'Boc') as a temporary N-terminal α-amino protecting group. The Boc group is removed with acid, such as trifluoroacetic acid (TFA). This forms a positively charged amino group in the presence of excess TFA (note that the amino group is not protonated in the image on the right), which is neutralized and coupled to the incoming activated amino acid. Neutralization can either occur prior to coupling or in situ during the basic coupling reaction.

The Boc/Bzl approach retains its usefulness in reducing peptide aggregation during synthesis. In addition, Boc/Bzl SPPS may be preferred over the Fmoc/tBu approach when synthesizing peptides containing base-sensitive moieties (such as depsipeptides), as treatment with base is required during the Fmoc deprotection step (see below).

Permanent side-chain protecting groups used during Boc/Bzl SPPS are typically benzyl or benzyl-based groups. Final removal of the peptide from the solid support occurs simultaneously with side chain deprotection using anhydrous hydrogen fluoride via hydrolytic cleavage. The final product is a fluoride salt which is relatively easy to solubilize. Scavengers such as cresol must be added to the HF in order to prevent reactive t-butyl cations from generating undesired products. A disadvantage of this approach is the potential for degradation of the peptide by hydrogen fluoride.

Fmoc/tBu SPPS

Cleavage of the Fmoc group. Treatment of the Fmoc-protected amine with piperidine results in proton abstraction from the methine group of the fluorenyl ring system. This leads to release of a carbamate, which decomposes into carbon dioxide (CO₂) and the free amine. Dibenzofulvene is also generated. This reaction is able to occur due to the acidity of the fluorenyl proton, resulting from stabilization of the aromatic anion formed. The dibenzofulvene by-product can react with nucleophiles such as the piperidine (which is in large excess), or potentially the released amine.

The use of N-terminal Fmoc protection allows for a milder deprotection scheme than used for Boc/Bzl SPPS, and this protection scheme is truly orthogonal under SPPS conditions. Fmoc deprotection utilizes a base, typically 20–50% piperidine in DMF. The exposed amine is therefore neutral, and consequently no neutralization of the peptide-resin is required, as in the case of the Boc/Bzl approach. The lack of electrostatic repulsion between the peptide chains can lead to increased risk of aggregation with Fmoc/tBu SPPS however. Because the liberated fluorenyl group is a chromophore, Fmoc deprotection can be monitored by UV absorbance of the reaction mixture, a strategy which is employed in automated peptide synthesizers.

The ability of the Fmoc group to be cleaved under relatively mild basic conditions while being stable to acid allows the use of side chain protecting groups such as Boc and tBu that can be removed in milder acidic final cleavage conditions (TFA) than those used for final cleavage in Boc/Bzl SPPS (HF). Scavengers such as water and triisopropylsilane (TIPS) are added during the final cleavage in order to prevent side reactions with reactive cationic species released as a result of side chain deprotection. The resulting crude peptide is obtained as a TFA salt, which is potentially more difficult to solubilize than the fluoride salts generated in Boc SPPS.

Fmoc/tBu SPPS is less atom-economical, as the fluorenyl group is much larger than the Boc group. Accordingly, prices for Fmoc amino acids were high until the large-scale piloting of one of the first synthesized peptide drugs, enfuvirtide, began in the 1990s, when market demand adjusted the relative prices of Fmoc- vs Boc- amino acids.

Other protecting groups

Benzyloxy-carbonyl

The (Z) group is another carbamate-type amine protecting group, first used by Max Bergmann in the synthesis of oligopeptides. It is removed under harsh conditions using HBr in acetic acid, or milder conditions of catalytic hydrogenation. While it has been used periodically for α-amine protection in peptide synthesis, it is almost exclusively used for side chain protection.

Alloc and miscellaneous groups

The allyloxycarbonyl (alloc) protecting group is sometimes used to protect an amino group (or carboxylic acid or alcohol group) when an orthogonal deprotection scheme is required. It is also sometimes used when conducting on-resin cyclic peptide formation, where the peptide is linked to the resin by a side-chain functional group. The Alloc group can be removed using tetrakis(triphenylphosphine)palladium(0).

For special applications like synthetic steps involving protein microarrays, protecting groups sometimes termed "lithographic" are used, which are amenable to photochemistry at a particular wavelength of light, and so which can be removed during lithographic types of operations.

Regioselective disulfide bond formation

The formation of multiple native disulfides remains challenging of native peptide synthesis by solid-phase methods. Random chain combination typically results in several products with nonnative disulfide bonds. Stepwise formation of disulfide bonds is typically the preferred method, and performed with thiol protecting groups. Different thiol protecting groups provide multiple dimensions of orthogonal protection. These orthogonally protected cysteines are incorporated during the solid-phase synthesis of the peptide. Successive removal of these groups, to allow for selective exposure of free thiol groups, leads to disulfide formation in a stepwise manner. The order of removal of the groups must be considered so that only one group is removed at a time.

Thiol protecting groups used in peptide synthesis requiring later regioselective disulfide bond formation must possess multiple characteristics.^{[citation needed][verification needed]} First, they must be reversible with conditions that do not affect the unprotected side chains. Second, the protecting group must be able to withstand the conditions of solid-phase synthesis. Third, the removal of the thiol protecting group must be such that it leaves intact other thiol protecting groups, if orthogonal protection is desired. That is, the removal of PG A should not affect PG B. Some of the thiol protecting groups commonly used include the acetamidomethyl (Acm), tert-butyl (But), 3-nitro-2-pyridine sulfenyl (NPYS), 2-pyridine-sulfenyl (Pyr), and trityl (Trt) groups. Importantly, the NPYS group can replace the Acm PG to yield an activated thiol.

Using this method, Kiso and coworkers reported the first total synthesis of insulin in 1993. In this work, the A-chain of insulin was prepared with following protecting groups in place on its cysteines: CysA6(But), CysA7(Acm), and CysA11(But), leaving CysA20 unprotected.

Microwave-assisted peptide synthesis

Microwave-assisted peptide synthesis has been used to complete long peptide sequences with high degrees of yield and low degrees of racemization.

Synthesizing long peptides

Stepwise elongation, in which the amino acids are connected step-by-step in turn, is ideal for small peptides containing between 2 and 100 amino acid residues. Another method is fragment condensation, in which peptide fragments are coupled. Although the former can elongate the peptide chain without racemization, the yield drops if only it is used in the creation of long or highly polar peptides. Fragment condensation is better than stepwise elongation for synthesizing sophisticated long peptides, but its use must be restricted in order to protect against racemization. Fragment condensation is also undesirable since the coupled fragment must be in gross excess, which may be a limitation depending on the length of the fragment.

A new development for producing longer peptide chains is chemical ligation: unprotected peptide chains react chemoselectively in aqueous solution. A first kinetically controlled product rearranges to form the amide bond. The most common form of native chemical ligation uses a peptide thioester that reacts with a terminal cysteine residue.

Other methods applicable for covalently linking polypeptides in aqueous solution include the use of split inteins, spontaneous isopeptide bond formation and sortase ligation.

In order to optimize synthesis of long peptides, a method was developed in Medicon Valley for converting peptide sequences.^{[citation needed]} The simple pre-sequence (e.g. Lysine (Lysn); Glutamic Acid (Glun); (LysGlu)n) that is incorporated at the C-terminus of the peptide to induce an alpha-helix-like structure. This can potentially increase biological half-life, improve peptide stability and inhibit enzymatic degradation without altering pharmacological activity or profile of action.

Cyclic peptides

On resin cyclization

Peptides can be cyclized on a solid support. A variety of cylization reagents can be used such as HBTU/HOBt/DIEA, PyBop/DIEA, PyClock/DIEA. Head-to-tail peptides can be made on the solid support. The deprotection of the C-terminus at some suitable point allows on-resin cyclization by amide bond formation with the deprotected N-terminus. Once cyclization has taken place, the peptide is cleaved from resin by acidolysis and purified.

The strategy for the solid-phase synthesis of cyclic peptides in not limited to attachment through Asp, Glu or Lys side chains. Cysteine has a very reactive sulfhydryl group on its side chain. A disulfide bridge is created when a sulfur atom from one Cysteine forms a single covalent bond with another sulfur atom from a second cysteine in a different part of the protein. These bridges help to stabilize proteins, especially those secreted from cells. Some researchers use modified cysteines using S-acetomidomethyl (Acm) to block the formation of the disulfide bond but preserve the cysteine and the protein's original primary structure.

Off-resin cyclization

Off-resin cyclization is a solid-phase synthesis of key intermediates, followed by the key cyclization in solution phase, the final deprotection of any masked side chains is also carried out in solution phase. This has the disadvantages that the efficiencies of solid-phase synthesis are lost in the solution phase steps, that purification from by-products, reagents and unconverted material is required, and that undesired oligomers can be formed if macrocycle formation is involved.

The use of pentafluorophenyl esters (FDPP, PFPOH) and BOP-Cl are useful for cyclising peptides.

Impact of health on intelligence

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Health can affect intelligence in various ways. Conversely, intelligence can affect health. Health effects on intelligence have been described as being among the most important factors in the origins of human group differences in IQ test scores and other measures of cognitive ability. Several factors can lead to significant cognitive impairment, particularly if they occur during pregnancy and childhood when the brain is growing and the blood–brain barrier of the child is less effective. Such impairment may sometimes be permanent, sometimes be partially or wholly compensated for by later growth.

Developed nations have implemented several health policies regarding nutrients and toxins known to influence cognitive function. These include laws requiring fortification of certain food products and laws establishing safe levels of pollutants (e.g. lead, mercury, and organochlorides). Comprehensive policy recommendations targeting reduction of cognitive impairment in children have been proposed.

Improvements in nutrition (often involving specific micronutrients) due to public policy changes have been implicated in IQ increases in many nations (as part of the overall Flynn effect), such as efforts fighting iodine deficiency in the U.S.

Nutrition

Malnutrition may occur during several periods of growth, such as pregnancy, during breastfeeding, infancy, or childhood. It may also happen due to deficiencies of different nutrients, such as micronutrients, protein or energy. This may cause different effects.

Timing

Some observers have argued that malnutrition during the first six months of life harms cognitive development much more than malnutrition later in life. However, a study from the Philippines argues that malnutrition in the second year of life may have a larger negative impact than malnutrition in the first year of life.

Intrauterine growth retardation

Undernutrition during pregnancy, and other factors, may cause intrauterine growth retardation (IUGR), which is one cause of low birth weight. However, it has been suggested that in IUGR the brain may be selectively spared. Brain growth is usually less affected than whole body weight or length. Several studies from developed nations have found that with the exception of extreme intrauterine growth retardation also affecting brain growth, and hypoxic injury, IUGR seems to have little or no measurable effect on mental performance and behavior in adolescence or adulthood. For example, acute undernutrition for a few months during the Dutch famine of 1944 caused a decrease in mean birthweight in certain areas. This was later associated with a change in performance on IQ tests for 18–19 years old Dutch males draftees from these areas compared to control areas. The subjects were exposed to famine prenatally but not after birth. During the famine, births decreased more among those with lower socioeconomic status (SES), whereas after the famine, there was a compensatory increase in births among those with lower SES. Since SES correlates with IQ, this may have hidden an effect caused by the undernutrition.

Breastfeeding

Studies often find higher IQ in children and adults who were breastfed. It has been proposed that omega-3 fatty acids in breast milk, known to be essential constituents of brain tissues, could at least partially account for an increase in IQ.

Recently, however, the longstanding belief that breastfeeding causes an increase in the IQ of offspring was challenged in a 2006 paper published in the British Medical Journal. The results indicated that mother's IQ, not breastfeeding, explained the differences in the IQ scores of offspring measured between ages 5 and 14. The results of this meta-analysis argued that prior studies had not controlled for the mother's IQ. Since mother's IQ was predictive of whether a child was breastfed, the study concluded that "breast feeding [itself] has little or no effect on intelligence in children." Instead, it was the mother's IQ that had a significant correlation with the IQ of her offspring, whether the offspring was breastfed or was not breastfed.

One study found that breastfeeding was linked to raised IQ (as much as 7 points when not controlling for maternal IQ) if the infants had an SNP coding for a "C" rather than G base within the FADS2 gene. Those with the "G" version showed no IQ advantage, suggesting a biochemical interaction of child's genes on the effect of breastfeeding. Other studies have failed to replicate any correlation between the FADS2 gene, breastfeeding and IQ, while others show a negative effect on IQ when combining bottled feeding, and the "G" version of FADS2.

Infancy

Two studies in Chile on 18-year-old high-school graduates found that nutritional status during the first year of life affected IQ, scholastic achievement, and brain volume.

Micronutrients and vitamin deficiencies

Micronutrient deficiencies (e.g. in iodine and iron) influence the development of intelligence and remain a problem in the developing world. For example, iodine deficiency causes a fall, in average, of 12 IQ points.

Policy recommendations to increase availability of micronutrient supplements have been made and justified in part by the potential to counteract intelligence-related developmental problems. For example, the Copenhagen consensus, states that lack of both iodine and iron has been implicated in impaired brain development, and this can affect enormous numbers of people: it is estimated that 2 billion people (one-third of the total global population) are affected by iodine deficiency, including 285 million 6- to 12-year-old children. In developing countries, it is estimated that 40% of children aged four and under suffer from anaemia because of insufficient iron in their diets.

A joint statement on vitamin and mineral deficiencies says that the severity of such deficiencies "means the impairment of hundreds of millions of growing minds and the lowering of national IQs."

Overall, studies investigating whether cognitive function in already iron-deficient children can be improved with iron supplements have produced mixed results, possibly because deficiency in critical growth periods may cause irreversible damage. However, several studies with better design have shown substantial benefits. One way to prevent iron deficiency is to give specific supplementation to children, for example as tablets. However, this is costly, distribution mechanisms are often ineffective, and compliance is low. Fortification of staple foods (cereals, flour, sugar, salt) to deliver micronutrients to children on a large scale is probably the most sustainable and affordable option, even though commitment from governments and the food industry is needed. Developed nations fortify several foods with various micronutrients.

Additional vitamin-mineral supplementation may have an effect also in the developed world. A study giving such supplementation to "working class," primarily Hispanic, 6–12-year-old children in the United States for 3 months found an average increase of 2 to 3 IQ points. Most of this can be explained by the very large increase of a subgroup of the children, presumably because these were not adequately nourished unlike the majority. The study suggests that parents of schoolchildren whose academic performance is substandard would be well advised to seek a nutritionally oriented physician for assessment of their children's nutritional status as a possible etiology.

More speculatively, other nutrients may prove important in the future. Vitamin B12 and folate may be important for cognitive function in old age. Fish oil supplement to pregnant and lactating mothers has been linked to increased cognitive ability in one study.

Another study found that pregnant women who consumed 340 grams of low-mercury containing fish with fatty acids per week have benefits that outweigh the risks for mercury poisoning. They were less likely to have children with low verbal IQ, motor coordination and behavioral problems. However, foods containing high amounts of mercury, such as shark, swordfish, king mackerel and tilefish, might cause mental retardation.

Protein and energy malnutrition

One study from a developing country, Guatemala, found that poor growth during infancy, rather than low birth weight, was negatively related to adolescent performance on cognitive and achievement tests. A later related very long term study looked at the effect of giving 6–24-month-old children in Guatemala a high protein-energy drink as a dietary supplement. A significantly positive and fairly substantial effects was found on increasing the probability of attending school and of passing the first grade, increasing the grade attained by age 13, increasing completed schooling attainment, and for adults aged 25–40 increasing IQ test scores.

Stunting

31% of children under the age of 5 in the developing world are moderately (height-for-age is below minus 2 standard deviations) or severely stunted (below minus 3 standard deviations). The prevalence was even higher previously since the worldwide prevalence of stunting is declining by about half of a percentage point each year. A study on stunted children aged 9–24 months in Jamaica found that when aged 17–18 years they had significantly poorer scores than a non-stunted group on cognitive and educational tests and psychosocial functioning. Giving a nutritional supplementation (1 kg milk based formula each week) to these already stunted children had no significant effect on later scores, but psychosocial stimulation (weekly play sessions with mother and child) had a positive effect.

Toxins

Industrial chemicals

Certain toxins, such as lead, mercury, toluene, and PCB are well-known causes of neuro-developmental disorders. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays.

Policies to manage lead differ between nations, particularly between the developed and developing world. Use of leaded gasoline has been reduced or eliminated in most developed nations, and lead levels in US children have been substantially reduced by policies relating to lead reduction. Even slightly elevated lead levels around the age of 24 months are associated with intellectual and academic performance deficits at age 10 years.

Certain, at least previously, widely used organochlorides, such as dioxins, DDT, and PCB, have been associated with cognitive deficits.

A Lancet review identified 201 chemicals with the ability to cause clinical neurotoxic effects in human adults, as described in the peer-reviewed scientific literature. Most of them are commonly used. Many additional chemicals have been shown to be neurotoxic in laboratory models. The article notes that children are more vulnerable and argues that new, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals in order to avoid the previous substantial before starting restrictions on usage. An appendix listed further industrial chemicals considered to be neurotoxic.

Alcohol and drugs

Fetal alcohol exposure, causing Fetal alcohol syndrome, is one of the leading known causes of mental retardation in the Western world.

Current cannabis use was found to be significantly correlated in a dose-dependent manner with a decline in IQ scores, during the effect of the use. However, no such decline was seen in subjects who had formerly been heavy cannabis users and had stopped taking the drug. The authors concluded that cannabis does not have a long-term effect on intelligence. However this is contradicted by the long term longitudinal study, carried out by Otago and Duke universities,which found that regular use of marijuana in teenage years affects IQ in adulthood even when the use stops. The drop in IQ was 8 points. Adults smoking marijuana had no lasting effect on IQ. Effects on fetal development are minimal when compared with the well-documented adverse effects of tobacco or alcohol use.

Maternal tobacco smoking during pregnancy is associated with increased activity, decreased attention, and diminished intellectual abilities. However, a recent study finds that maternal tobacco smoking has no direct causal effect on the child's IQ. Adjusting for maternal cognitive ability as measured by IQ and education eliminated the association between lower IQ and tobacco smoking. But another study instead looking at the relationship between environmental tobacco smoke exposure, measured with a blood biomarker, and cognitive abilities among U.S. children and adolescents 6–16 years of age, found an inverse association between exposure and cognitive ability among children even at extremely low levels of exposure. The study controlled for sex, race, region, poverty, parent education and marital status, ferritin, and blood lead concentration.

Healthcare during pregnancy and childbirth

Healthcare during pregnancy and childbirth, access to which is often governed by policy, also influences cognitive development. Preventable causes of low intelligence in children include infectious diseases such as meningitis, parasites, and cerebral malaria, prenatal drug and alcohol exposure, newborn asphyxia, low birth weight, head injuries, and endocrine disorders. A direct policy focus on determinants of childhood cognitive ability has been urged.

Stress

A recent theory suggests that early childhood stress may affect the developing brain and cause negative effects. Exposure to violence in childhood has been associated with lower school grades and lower IQ in children of all races. A group of largely African American urban first-grade children and their caregivers were evaluated using self-report, interview, and standardized tests, including IQ tests. The study reported that exposure to violence and trauma-related distress in young children were associated with substantial decrements in IQ and reading achievement. Exposure to Violence or Trauma lead to a 7.5-point (SD, 0.5) decrement in IQ and a 9.8-point (SD, 0.66) decrement in reading achievement.

Violence may have a negative impact on IQ, or IQ may be protective against violence. The causal mechanism and direction of causation is unknown. Neighborhood risk has been related to lower school grades for African-American adolescents in another study from 2006.

Infectious diseases

A 2010 study by Eppig, Fincher and Thornhill found a close correlation between the infectious disease burden in a country and the average IQ of its population. The researchers found that when disease was controlled for, IQ showed no correlation with other variables such as educational and nutritional levels. Since brain development requires a very high proportion of all the body's energy in newborns and children, the researchers argue that fighting infection reduces children's IQ potential. The Eppig research may help to explain the Flynn effect, the rise in intelligence noted in rich countries. They also tested other hypotheses as well, including genetic explanations, concluding that infectious disease was "the best predictor". Christopher Hassall and Thomas Sherratt repeated the analysis, and concluded "that infectious disease may be the only really important predictor of average national IQ".

In order to mitigate the effects of education on IQ, Eppig, Fincher & Thornhill (2010) repeated their analysis across the United States where standardized and compulsory education exists. The correlation between infectious disease and average IQ was confirmed, and they concluded that the "evidence suggests that infectious disease is a primary cause of the global variation in human intelligence".

Tropical infectious diseases

Malaria affects 300–500 million persons each year, mostly children under age five in Africa, causing widespread anemia during a period of rapid brain development and also direct brain damage from cerebral malaria to which children are more vulnerable. A 2006 systematic review found that Plasmodium falciparum infection causes cognitive deficits in both the short- and long-term. Policies aimed at malaria reduction may have cognitive benefits. It has been suggested that the future economic and educational development of Africa critically depends on the eradication of malaria.

Roundworms infect hundreds of millions of people. There is evidence that high intensities of worms in the intestines can affect mental performance, but a systematic review in 2000 and a 2009 update found that there was insufficient evidence to show that deworming treatments improve cognitive performance or school performance in children.

HIV infection in children in sub-Saharan Africa affects their motor development, but there is insufficient evidence to show a slowing of language development.

Effects of other diseases

There are numerous diseases affecting the central nervous system which can cause cognitive impairment. Many of these are associated with aging. Some common examples include Alzheimer's disease and Multi-infarct dementia. Many diseases may be neurological or psychiatric and may primarily affect the brain. Others may affect many other organs, like HIV, Hashimoto's thyroiditis causing hypothyroidism, or cancer. According to a 2015 report in The American Scholar, an assortment of neglected tropical diseases as well as some recently identified pathogens such as Pseudo-nitzschia have also been found to erode human intelligence.

Major depression, affecting about 16% of the population on at least one occasion in their lives and the leading cause of disability in North America, may give symptoms similar to dementia. Patients treated for depression score higher on IQ tests than before treatment.

Myopia and hyperopia

A 2008 literature review writes that studies in several nations have found a relationship between myopia and higher IQ and between myopia and school achievement. Several, but not all, studies have found hyperopia to be associated with lower IQ and school achievements. A common explanation for myopia is near-work. Regarding the relationship to IQ, several explanations have been proposed. One is that the myopic child is better adapted at reading, and reads and studies more, which increases intelligence. The reverse explanation is that the intelligent and studious child reads more which causes myopia. Another is that the myopic child have an advantage at IQ testing which is near work because of less eye strain. Still another explanation is that pleiotropic gene(s) affect the size of both brain and eyes simultaneously. A study of Chinese schoolchildren found that after controlling for age, gender, school, parental myopia, father’s education, and books read per week, myopia was still associated with high nonverbal IQ. Nonverbal IQ was a more important explanation than books read per week.

Other associations

Long working hours (55 vs. 40) was associated with decreased scores on cognitive tests in a 5-year study on midlife British civil servants.

Heritability of IQ

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Research on heritability of IQ implies, from the similarity of IQ in closely related persons, the proportion of variance of IQ among individuals in a study population that is associated with genetic variation within that population. This provides a maximum estimate of genetic versus environmental influence for phenotypic variation in IQ in that population as environmental factors may be correlated with genetic factors. "Heritability", in this sense, "refers to the genetic contribution to variance within a population and in a specific environment". In other words, heritability is a mathematical estimate that indicates an upper bound on how much of a trait's variation can be attributed to genes. There has been significant controversy in the academic community about the heritability of IQ since research on the issue began in the late nineteenth century. Intelligence in the normal range is a polygenic trait, meaning that it is influenced by more than one gene.

The heritability of IQ for adults is between 57% and 73% with some more-recent estimates as high as 80% and 86%. Genome-wide association studies have identified inherited genome sequence differences that account for 20% of the 50% of the genetic variation that contributes to heritability. IQ goes from being weakly correlated with genetics, for children, to being strongly correlated with genetics for late teens and adults. The heritability of IQ increases with age and reaches an asymptote at 18–20 years of age and continues at that level well into adulthood. This phenomenon is known as the Wilson Effect. Recent studies suggest that family and parenting characteristics are not significant contributors to variation in IQ scores; however, poor prenatal environment, malnutrition and disease can have deleterious effects.

Heritability and caveats

"Heritability" is defined as the proportion of variance in a trait which is attributable to genetic variation within a defined population in a specific environment. Heritability takes a value ranging from 0 to 1; a heritability of 1 indicates that all variation in the trait in question is genetic in origin and a heritability of 0 indicates that none of the variation is genetic. The determination of many traits can be considered primarily genetic under similar environmental backgrounds. For example, a 2006 study found that adult height has a heritability estimated at 0.80 when looking only at the height variation within families where the environment should be very similar. Other traits have lower heritabilities, which indicate a relatively larger environmental influence. For example, a twin study on the heritability of depression in men calculated it as 0.29, while it was 0.42 for women in the same study. Contrary to popular belief, two parents of higher IQ will not necessarily produce offspring of equal or higher intelligence. In fact, according to the concept of regression toward the mean, parents whose IQ is at either extreme are more likely to produce offspring with IQ closer to the mean (or average).

Caveats

There are a number of points to consider when interpreting heritability:

• Heritability measures the proportion of variation in a trait that can be attributed to genes, and not the proportion of a trait caused by genes. Thus, if the environment relevant to a given trait changes in a way that affects all members of the population equally, the mean value of the trait will change without any change in its heritability (because the variation or differences among individuals in the population will stay the same). This has evidently happened for height: the heritability of stature is high, but average heights continue to increase. Thus, even in developed nations, a high heritability of a trait does not necessarily mean that average group differences are due to genes. Some have gone further, and used height as an example in order to argue that "even highly heritable traits can be strongly manipulated by the environment, so heritability has little if anything to do with controllability."
• A common error is to assume that a heritability figure is necessarily unchangeable. The value of heritability can change if the impact of environment (or of genes) in the population is substantially altered. If the environmental variation encountered by different individuals increases, then the heritability figure would decrease. On the other hand, if everyone had the same environment, then heritability would be 100%. The population in developing nations often has more diverse environments than in developed nations. This would mean that heritability figures would be lower in developing nations. Another example is phenylketonuria which previously caused mental retardation for everyone who had this genetic disorder and thus had a heritability of 100%. Today, this can be prevented by following a modified diet, resulting in a lowered heritability.
• A high heritability of a trait does not mean that environmental effects such as learning are not involved. Vocabulary size, for example, is very substantially heritable (and highly correlated with general intelligence) although every word in an individual's vocabulary is learned. In a society in which plenty of words are available in everyone's environment, especially for individuals who are motivated to seek them out, the number of words that individuals actually learn depends to a considerable extent on their genetic predispositions and thus heritability is high.
• Since heritability increases during childhood and adolescence, and even increases greatly between 16–20 years of age and adulthood, one should be cautious drawing conclusions regarding the role of genetics and environment from studies where the participants are not followed until they are adults. Furthermore, there may be differences regarding the effects on the g-factor and on non-g factors, with g possibly being harder to affect and environmental interventions disproportionately affecting non-g factors.

Estimates

Various studies have found the heritability of IQ to be between 0.7 and 0.8 in adults and 0.45 in childhood in the United States. It may seem reasonable to expect that genetic influences on traits like IQ should become less important as one gains experiences with age. However, that the opposite occurs is well documented. Heritability measures in infancy are as low as 0.2, around 0.4 in middle childhood, and as high as 0.8 in adulthood. One proposed explanation is that people with different genes tend to seek out different environments that reinforce the effects of those genes. The brain undergoes morphological changes in development which suggests that age-related physical changes could also contribute to this effect.

A 1994 article in Behavior Genetics based on a study of Swedish monozygotic and dizygotic twins found the heritability of the sample to be as high as 0.80 in general cognitive ability; however, it also varies by trait, with 0.60 for verbal tests, 0.50 for spatial and speed-of-processing tests, and 0.40 for memory tests. In contrast, studies of other populations estimate an average heritability of 0.50 for general cognitive ability.

In 2006, The New York Times Magazine listed about three quarters as a figure held by the majority of studies.

Shared family environment

There are some family effects on the IQ of children, accounting for up to a quarter of the variance. However, adoption studies show that by adulthood adoptive siblings aren't more similar in IQ than strangers, while adult full siblings show an IQ correlation of 0.24. However, some studies of twins reared apart (e.g. Bouchard, 1990) find a significant shared environmental influence, of at least 10% going into late adulthood. Judith Rich Harris suggests that this might be due to biasing assumptions in the methodology of the classical twin and adoption studies.

There are aspects of environments that family members have in common (for example, characteristics of the home). This shared family environment accounts for 0.25-0.35 of the variation in IQ in childhood. By late adolescence it is quite low (zero in some studies). There is a similar effect for several other psychological traits. These studies have not looked into the effects of extreme environments such as in abusive families.

The American Psychological Association's report "Intelligence: Knowns and Unknowns" (1995) states that there is no doubt that normal child development requires a certain minimum level of responsible care. Severely deprived, neglectful, or abusive environments must have negative effects on a great many aspects of development, including intellectual aspects. Beyond that minimum, however, the role of family experience is in serious dispute. There is no doubt that such variables as resources of the home and parents' use of language are correlated with children's IQ scores, but such correlations may be mediated by genetic as well as (or instead of) environmental factors. But how much of that variance in IQ results from differences between families, as contrasted with the varying experiences of different children in the same family? Recent twin and adoption studies suggest that while the effect of the shared family environment is substantial in early childhood, it becomes quite small by late adolescence. These findings suggest that differences in the life styles of families whatever their importance may be for many aspects of children's lives make little long-term difference for the skills measured by intelligence tests.

Non-shared family environment and environment outside the family

Although parents treat their children differently, such differential treatment explains only a small amount of non-shared environmental influence. One suggestion is that children react differently to the same environment due to different genes. More likely influences may be the impact of peers and other experiences outside the family. For example, siblings grown up in the same household may have different friends and teachers and even contract different illnesses. This factor may be one of the reasons why IQ score correlations between siblings decreases as they get older.

Malnutrition and diseases

Certain single-gene genetic disorders can severely affect intelligence. Phenylketonuria is an example, with publications demonstrating the capacity of phenylketonuria to produce a reduction of 10 IQ points on average. Meta-analyses have found that environmental factors, such as iodine deficiency, can result in large reductions in average IQ; iodine deficiency has been shown to produce a reduction of 12.5 IQ points on average.

Heritability and socioeconomic status

The APA report "Intelligence: Knowns and Unknowns" (1995) also stated that:

"We should note, however, that low-income and non-white families are poorly represented in existing adoption studies as well as in most twin samples. Thus it is not yet clear whether these studies apply to the population as a whole. It remains possible that, across the full range of income and ethnicity, between-family differences have more lasting consequences for psychometric intelligence."

A study (1999) by Capron and Duyme of French children adopted between the ages of four and six examined the influence of socioeconomic status (SES). The children's IQs initially averaged 77, putting them near retardation. Most were abused or neglected as infants, then shunted from one foster home or institution to the next. Nine years later after adoption, when they were on average 14 years old, they retook the IQ tests, and all of them did better. The amount they improved was directly related to the adopting family's socioeconomic status. "Children adopted by farmers and laborers had average IQ scores of 85.5; those placed with middle-class families had average scores of 92. The average IQ scores of youngsters placed in well-to-do homes climbed more than 20 points, to 98."

Stoolmiller (1999) argued that the range of environments in previous adoption studies was restricted. Adopting families tend to be more similar on, for example, socio-economic status than the general population, which suggests a possible underestimation of the role of the shared family environment in previous studies. Corrections for range restriction to adoption studies indicated that socio-economic status could account for as much as 50% of the variance in IQ.

On the other hand, the effect of this was examined by Matt McGue and colleagues (2007), who wrote that "restriction in range in parent disinhibitory psychopathology and family socio-economic status had no effect on adoptive-sibling correlations [in] IQ."

Turkheimer and colleagues (2003) argued that the proportions of IQ variance attributable to genes and environment vary with socioeconomic status. They found that in a study on seven-year-old twins, in impoverished families, 60% of the variance in early childhood IQ was accounted for by the shared family environment, and the contribution of genes is close to zero; in affluent families, the result is almost exactly the reverse.

In contrast to Turkheimer (2003), a study by Nagoshi and Johnson (2005) concluded that the heritability of IQ did not vary as a function of parental socioeconomic status in the 949 families of Caucasian and 400 families of Japanese ancestry who took part in the Hawaii Family Study of Cognition.

Asbury and colleagues (2005) studied the effect of environmental risk factors on verbal and non-verbal ability in a nationally representative sample of 4-year-old British twins. There was not any statistically significant interaction for non-verbal ability, but the heritability of verbal ability was found to be higher in low-SES and high-risk environments.

Harden and colleagues (2007) investigated adolescents, most 17 years old, and found that, among higher income families, genetic influences accounted for approximately 55% of the variance in cognitive aptitude and shared environmental influences about 35%. Among lower income families, the proportions were in the reverse direction, 39% genetic and 45% shared environment."

Rushton and Jensen (2010) criticized many of these studies for being done on children or adolescents. They argued that heritability increases during childhood and adolescence, and even increases greatly between 16–20 years of age and adulthood, so one should be cautious drawing conclusions regarding the role of genetics from studies where the participants are not adults. Furthermore, the studies typically did not examine if IQ gains due to adoption were on the general intelligence factor (g). When the studies by Capron and Duyme were re-examined, IQ gains from being adopted into high SES homes were on non-g factors. By contrast, the adopted children's g mainly depended on their biological parents SES, which implied that g is more difficult to environmentally change. The most cited adoption projects that sought to estimate the heritability of IQ were those of Texas, Colorado and Minnesota that were started in the 1970s. These studies showed that while the adoptive parents' IQ does correlate with adoptees' IQ in early life, when the adoptees reach adolescence the correlation has faded and disappeared. The correlation with the biological parent seemed to explain most of the variation.

A 2011 study by Tucker-Drob and colleagues reported that at age 2, genes accounted for approximately 50% of the variation in mental ability for children being raised in high socioeconomic status families, but genes accounted for negligible variation in mental ability for children being raised in low socioeconomic status families. This gene-environment interaction was not apparent at age 10 months, suggesting that the effect emerges over the course of early development.

A 2012 study based on a representative sample of twins from the United Kingdom, with longitudinal data on IQ from age two to age fourteen, did not find evidence for lower heritability in low-SES families. However, the study indicated that the effects of shared family environment on IQ were generally greater in low-SES families than in high-SES families, resulting in greater variance in IQ in low-SES families. The authors noted that previous research had produced inconsistent results on whether or not SES moderates the heritability of IQ. They suggested three explanations for the inconsistency. First, some studies may have lacked statistical power to detect interactions. Second, the age range investigated has varied between studies. Third, the effect of SES may vary in different demographics and different countries.

A 2017 King's College London study suggests that genes account for nearly 50 per cent of the differences between whether children are socially mobile or not.

Maternal (fetal) environment

A meta-analysis by Devlin and colleagues (1997) of 212 previous studies evaluated an alternative model for environmental influence and found that it fits the data better than the 'family-environments' model commonly used. The shared maternal (fetal) environment effects, often assumed to be negligible, account for 20% of covariance between twins and 5% between siblings, and the effects of genes are correspondingly reduced, with two measures of heritability being less than 50%. They argue that the shared maternal environment may explain the striking correlation between the IQs of twins, especially those of adult twins that were reared apart. IQ heritability increases during early childhood, but whether it stabilizes thereafter remains unclear. These results have two implications: a new model may be required regarding the influence of genes and environment on cognitive function; and interventions aimed at improving the prenatal environment could lead to a significant boost in the population's IQ.

Bouchard and McGue reviewed the literature in 2003, arguing that Devlin's conclusions about the magnitude of heritability is not substantially different from previous reports and that their conclusions regarding prenatal effects stands in contradiction to many previous reports. They write that:

Chipuer et al. and Loehlin conclude that the postnatal rather than the prenatal environment is most important. The Devlin et al. (1997a) conclusion that the prenatal environment contributes to twin IQ similarity is especially remarkable given the existence of an extensive empirical literature on prenatal effects. Price (1950), in a comprehensive review published over 50 years ago, argued that almost all MZ twin prenatal effects produced differences rather than similarities. As of 1950 the literature on the topic was so large that the entire bibliography was not published. It was finally published in 1978 with an additional 260 references. At that time Price reiterated his earlier conclusion (Price, 1978). Research subsequent to the 1978 review largely reinforces Price’s hypothesis (Bryan, 1993; Macdonald et al., 1993; Hall and Lopez-Rangel, 1996; see also Martin et al., 1997, box 2; Machin, 1996).

Dickens and Flynn model

Dickens and Flynn (2001) argued that the "heritability" figure includes both a direct effect of the genotype on IQ and also indirect effects where the genotype changes the environment, in turn affecting IQ. That is, those with a higher IQ tend to seek out stimulating environments that further increase IQ. The direct effect can initially have been very small but feedback loops can create large differences in IQ. In their model an environmental stimulus can have a very large effect on IQ, even in adults, but this effect also decays over time unless the stimulus continues. This model could be adapted to include possible factors, like nutrition in early childhood, that may cause permanent effects.

The Flynn effect is the increase in average intelligence test scores by about 0.3% annually, resulting in the average person today scoring 15 points higher in IQ compared to the generation 50 years ago. This effect can be explained by a generally more stimulating environment for all people. The authors suggest that programs aiming to increase IQ would be most likely to produce long-term IQ gains if they taught children how to replicate outside the program the kinds of cognitively demanding experiences that produce IQ gains while they are in the program and motivate them to persist in that replication long after they have left the program. Most of the improvements have allowed for better abstract reasoning, spatial relations, and comprehension. Some scientists have suggested that such enhancements are due to better nutrition, better parenting and schooling, as well as exclusion of the least intelligent, genetically inferior, people from reproduction. However, Flynn and a group of other scientists share the viewpoint that modern life implies solving many abstract problems which leads to a rise in their IQ scores.

Influence of genes on IQ stability

Recent research has illuminated genetic factors underlying IQ stability and change. Genome-wide association studies have demonstrated that the genes involved in intelligence remain fairly stable over time. Specifically, in terms of IQ stability, "genetic factors mediated phenotypic stability throughout this entire period [age 0 to 16], whereas most age-to-age instability appeared to be due to non-shared environmental influences". These findings have been replicated extensively and observed in the United Kingdom, the United States, and the Netherlands. Additionally, researchers have shown that naturalistic changes in IQ occur in individuals at variable times.

Influence of parents genes that are not inherited

Kong reports that, "Nurture has a genetic component, i.e. alleles in the parents affect the parents' phenotypes and through that influence the outcomes of the child." These results were obtained through a meta-analysis of educational attainment and polygenic scores of non-transmitted alleles. Although the study deals with educational attainment and not IQ, these two are strongly linked.

Spatial ability component of IQ

Spatial ability has been shown to be unifactorial (a single score accounts well for all spatial abilities), and is 69% heritable in a sample of 1,367 twins from the ages 19 through 21. Further only 8% of spatial ability can be accounted for by a shared environmental factors like school and family. Of the genetically determined portion of spatial ability, 24% is shared with verbal ability (general intelligence) and 43% was specific to spatial ability alone.

Molecular genetic investigations

A 2009 review article identified over 50 genetic polymorphisms that have been reported to be associated with cognitive ability in various studies, but noted that the discovery of small effect sizes and lack of replication have characterized this research so far. Another study attempted to replicate 12 reported associations between specific genetic variants and general cognitive ability in three large datasets, but found that only one of the genotypes was significantly associated with general intelligence in one of the samples, a result expected by chance alone. The authors concluded that most reported genetic associations with general intelligence are probably false positives brought about by inadequate sample sizes, but see. Arguing that common genetic variants explain much of the variation in general intelligence, they suggested that the effects of individual variants are so small that very large samples are required to reliably detect them. Genetic diversity within individuals is heavily correlated with IQ.

A novel molecular genetic method for estimating heritability calculates the overall genetic similarity (as indexed by the cumulative effects of all genotyped single nucleotide polymorphisms) between all pairs of individuals in a sample of unrelated individuals and then correlates this genetic similarity with phenotypic similarity across all the pairs. A study using this method estimated that the lower bounds for the narrow-sense heritability of crystallized and fluid intelligence are 40% and 51%, respectively. A replication study in an independent sample confirmed these results, reporting a heritability estimate of 47%. These findings are compatible with the view that a large number of genes, each with only a small effect, contribute to differences in intelligence.

Correlations between IQ and degree of genetic relatedness

The relative influence of genetics and environment for a trait can be calculated by measuring how strongly traits covary in people of a given genetic (unrelated, siblings, fraternal twins, or identical twins) and environmental (reared in the same family or not) relationship. One method is to consider identical twins reared apart, with any similarities which exists between such twin pairs attributed to genotype. In terms of correlation statistics, this means that theoretically the correlation of tests scores between monozygotic twins would be 1.00 if genetics alone accounted for variation in IQ scores; likewise, siblings and dizygotic twins share on average half of their alleles and the correlation of their scores would be 0.50 if IQ were affected by genes alone (or greater if, as is undoubtedly the case, there is a positive correlation between the IQs of spouses in the parental generation). Practically, however, the upper bound of these correlations are given by the reliability of the test, which is 0.90 to 0.95 for typical IQ tests.

If there is biological inheritance of IQ, then the relatives of a person with a high IQ should exhibit a comparably high IQ with a much higher probability than the general population. In 1982, Bouchard and McGue reviewed such correlations reported in 111 original studies in the United States. The mean correlation of IQ scores between monozygotic twins was 0.86, between siblings 0.47, between half-siblings 0.31, and between cousins 0.15.

The 2006 edition of Assessing adolescent and adult intelligence by Alan S. Kaufman and Elizabeth O. Lichtenberger reports correlations of 0.86 for identical twins raised together compared to 0.76 for those raised apart and 0.47 for siblings. These number are not necessarily static. When comparing pre-1963 to late 1970s data, researches DeFries and Plomin found that the IQ correlation between parent and child living together fell significantly, from 0.50 to 0.35. The opposite occurred for fraternal twins.

It should be noted that every one of these studies presented next contains estimates of only two of the three factors which are relevant. The three factors are G, E, and GxE. Since there is no possibility of studying equal environments in a manner comparable to using identical twins for equal genetics, the GxE factor can not be isolated. Thus the estimates are actually of G+GxE and E. Although this may seem like nonsense, it is justified by the unstated assumption that GxE=0. It is also the case that the values shown below are r correlations and not r(squared), proportions of variance. Numbers less than one are smaller when squared. The next to last number in the list below refers to less than 5% shared variance between a parent and child living apart.
Another summary:

• Same person (tested twice) .95 next to
• Identical twins—Reared together .86
• Identical twins—Reared apart .76
• Fraternal twins—Reared together .55
• Fraternal twins—Reared apart .35
• Biological siblings—Reared together .47
• Biological siblings—Reared apart .24
• Biological siblings—Reared together—Adults .24 
• Unrelated children—Reared together—Children .28
• Unrelated children—Reared together—Adults .04
• Cousins .15
• Parent-child—Living together .42
• Parent-child—Living apart .22
• Adoptive parent–child—Living together .19

Between-group heritability

Although IQ differences between individuals are shown to have a large hereditary component, it does not follow that mean group-level disparities (between-group differences) in IQ necessarily have a genetic basis. The Flynn effect is one example where there is a large difference between groups (past and present) with little or no genetic difference. An analogy, attributed to Richard Lewontin, illustrates this point:

Suppose two handfuls are taken from a sack containing a genetically diverse variety of corn, and each grown under carefully controlled and standardized conditions, except that one batch is lacking in certain nutrients that are supplied to the other. After several weeks, the plants are measured. There is variability of growth within each batch, due to the genetic variability of the corn. Given that the growing conditions are closely controlled, nearly all the variation in the height of the plants within a batch will be due to differences in their genes. Thus, within populations, heritabilities will be very high. Nevertheless, the difference between the two groups is due entirely to an environmental factor—differential nutrition. Lewontin didn't go so far as to have the one set of pots painted white and the other set black, but you get the idea. The point of the example, in any case, is that the causes of between-group differences may in principle be quite different from the causes of within-group variation.

Arthur Jensen has written in agreement that this is technically correct, but he has also stated that a high heritability increases the probability that genetics play a role in average group differences.