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Abstract

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

Genetic factors have long been recognized as contributors to variantion in behaviour both within the normal span and as mental diseases. The first attempts to make behaviour the subject of scientific genetic studies used likeness between twins and other relatives to confirm heredity. Later heritability has been used as a quantitative estimate of the genetic part of the variance. Attempts to localize genetic factors became possible when associations between phenotypic aberrations and karyotype were observed. Inborn errors of metabolism further confirmed that specific metabolic deficits could influence behaviour.

Many kinds of common mental deficiencies such as senile dementia have a heterogeneous background, and so have normal variations in talents and personality. The mapping of the human genome, the availability of an unlimited number of genetic markers and efficient statistical tools promised ample discoveries of genes behind the variation. The expectations have not been fulfilled and more subtle influences on gene expression have to be assumed. Topics that are taken up include genomic imprinting, brain activation patterns, the importance of neurotransmitter regulation and non-additive interactions between genes and environment.

To understand the genetic mechanisms that cause individual differences in behaviour is among the most difficult tasks to be tackled by geneticists. There is no specific locus – a specific gene for mathematical, musical ability or language ability does not exist – only an unknown number of genes interacting with each other or with opportunities afforded by the environment, and the same gene may be important for many different behaviours.

In more than 100 years thoughts concerning personality, idiosyncrasies and mental diseases have occupied scientists interested in genetics. One of the first to make observations and experiments was Francis Galton (1822–1911) who was active already before the Mendelian laws were known. He observed the two different kinds of twins; the monozygotic ones developing from a single zygote, always of the same sex and confusingly alike, and the dizygotic of same or unlike sex and no more alike than ordinary siblings. Galton observed that the personality of monozygous twins was more alike than that of the dizygotes.

Heritability

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

During the 20th century the analyses of phenotypic likeness were extended to other relatives, parent–offspring, separated twins and adoptees with biological and adoptive family members.

The concept of heritability was first introduced in animal breeding by Jay Lush, professor at Ames in Iowa, USA. For a specified group of animals heritability estimates the part of the phenotypic variance that is due to genetic variation; more precisely the additive genetic part that can be used in selective breeding. The remaining part is due to non-additive effects such as dominance and epistatic interactions and to environmental influences. The heritability measurement was soon introduced also in human genetics for measurable traits, usually in the broad sense where all genetic influences are included. It can also be estimated for threshold characters where only two outcomes, normal and aberrant, can be observed. The assumption is that the phenotypic state is a manifestation of an underlying continuous liability, where the individual value is partly decided by genetic factors.

The measurement of heritability has been criticized both for being used in a faulty manner and for not being general. An incorrect way is to use a high heritability within groups to assign differences between groups to genetic causes. A difference between distribution and mean for groups can never be proved genetic by heritability within groups. This has caused fierce controversies, in particular in the case of IQ (Rose et al. 1984, 2009).

But also proper use of heritability to partition different parts of the variance within a group of individuals can be hazardous. Heritability is a quotient between genetic and total phenotypic variance, and none of these are fixed parameters. A genetically homogeneous group has small genetic variance and thus low heritability, but so has also a group with large non-genetic variation. Heritability alone cannot discern between such situations, and for a certain trait it is not a fixed quantity. In spite of these difficulties the heritability concept has been much used in behavioral genetics, which is legitimate as long as the data source is properly defined.

One further item of interest is the importance of early environment and non-genetic family influence. Studies have been made in two ways: likeness among separated monozygous twins and that of adoptees with biological and adoptive parents.

There is a trend from Galton over the geneticist H. J. Muller to later studies of twins. Monozygous twins are seldom separated but one pair of grown up girls was described by Muller in the 1930s. Lately in MISTRA (Minnesota Study of Twins Reared Apart) A. Tellegen and T. Bouchard have obtained around a hundred segregated pairs by means of advertising and have performed mental and physical tests of all kinds (Bouchard et al. 1990). The results confirm other studies in that most personality traits have a heritability of 0.5 or more and that the influence of home environment is small and transient. At the end of childhood it is almost zero. The constancy of heritabilities up to old ages has been studied with data from the Swedish Twin Register (Pedersen et al. 1992).

The possibilities for obtaining large numbers of adoptee data were good in Scandinavia for children born in the 1920s and 1930s. These data have been used to study misbehaviours such as criminal offences and intemperance that could be found in registers kept by authorities. These studies unanimously find genetic influences, shown by the greater likeness with biological families than with adoptive ones (Mednick et al 1984; Cloninger et al. 1981).

Longitudinal studies of several personality traits such as verbal and spatial ability, memory and openness in adoptees have been made in the Colorado Adoption Project from two years of age up to adolescence (DeFries et al. 1994). The same pattern of decreasing likeness to the adoptive parents and increased likeness to the biological parents were found.

Chromosomal number aberrations

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

Estimates of heritability do not indicate the nature of the genetical factors that influence the phenotype. Such analyses were not possible until cytological and molecular techniques became more advanced. The human chromosome number was not settled until 1956 (Tjio and Levan 1956) and very soon thereafter the most common type of mental retardation, Down's syndrome, was found to be caused by an extra copy of chromosome 21. Other supernumerary autosomes always result in serious developmental defects and carriers usually are aborted.

For the XY-pair, however, lost or added chromosomes are not uncommon. A supernumerary X can give rise to XXX or XXY, an extra Y to XYY, all in about one in a thousand births. The supernumeraries are usually accompanied by somewhat retarded mental capacity, fertility problems for XXY boys and a stature over 180 cm for both XXY and XYY boys. The XYY karyotype was first observed in an institution for violent criminals and was therefore assumed to be predetermined to antisocial behaviour. This view has been much modified, but generally the XYY men seem to be at a higher risk for criminal disposition, although seldom of a severe kind.

The XO karyotype with one single unpaired X is, although mostly aborted, found in about one in 3000 girls. These, showing Turner's syndrome, have normal verbal intelligence but their visuospatial capacities are poor. They are of small stature, with thick webbed neck and degenerate ovaries. They can have their single X either from father or mother. It is now possible to decide which is the case, and a clear personality difference has been found between these types (Skuse et al. 1997). Those with a maternal X are more demanding and have poorer social skill than those with a paternal X. The difference may be due to imprinting effects which will be discussed later.

Monogenetic defects

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

There are more than 300 cases known where mental retardation is included among the symptoms of metabolic genetic diseases caused by single mutations. Some are autosomal, recessive as PKUor dominant as Huntington's disease, but a surprisingly high proportion is sex-linked, such as fragile-X and Lesch–Nyhans syndrome. They may appear early or later in life.

PKU, phenylketonuria, can be caused by several different mutations in a gene on chromosome 12. In the 1930s PKU was studied by A. Følling who showed that in untreated cases severe mental retardation, small heads, light skin and hair are typical. This disease is the best example of how knowledge of metabolic function can lead to remedy. In mutants with a non-functioning phenylalanine hydroxylase the amino acid phenylalanine cannot be transfered to tyrosine. Phenylalanine is an essential amino acid which is supplied from many kinds of food. When a surplus of phenylalanine is accumulated it causes damage in the brain by destroying the myelin sheaths of nerves. A well balanced diet that starts immediately after birth allows a normal development. Nevertheless, even symptom-free PKU-women can get children with defects, mental or otherwise, caused by too high pre-natal level of phenylalanine.

Huntington's disease and fragile-X are both mental diseases where a gene is malfunctioning because of too many copies of certain nucleotide triplets. This may give rise to disease when the number of such repeats for unknown reasons increases up to several hundreds, disturbing the functioning of nearby genes. In Huntington's disease it is a triplet of CAG within a gene on chromosome 4 that is expanded. The normal numbers are 10 to 26. The number may increase, mostly during transmission from the father, and offspring with 40 or more repeats become affected by the disease, usually after the age of 35 years. The gene codes for a protein named huntingtin which affects the brain, destroying tissues mostly in corpus striatum.

In fragile-X the expansion of the triplet CGG can go on during several generations. The location is in the 5′-end of the sex-linked gene FMR-l, normally active in the brain, where transcription is prevented by the expansion. The normal number of repeats is 6–50. In so called premutations the number is increased to 50–230 but causes no symptoms in carriers, irrespective if they are male or female. Further expansions occur only in female carriers and can reach up to 1000 copies. Males with these high numbers show the fragile-X syndrome of mental retardation and a typical physiognomy with long face and protruding ears. Female heterozygotes are more rarely affected.

Lesch–Nyhan's syndrome is caused by a non-functioning enzyme, HPRT (hypoxantine phosphoribosyl transferase), which is necessary for synthesis of RNA. The disease is rare and only boys are affected. They are subject to learning difficulties and a tendency to self-mutilation.

Complex traits

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

Alzheimer's disease causes no less than half of all cases of dementia which befalls 15% of people over 80 years. Impairment of the brain is caused by extracellular plaques of amyloid beta-peptide and tangles of abnormal neurofibrillary bundles. It can be definitely diagnosed only after studies of brain autopsies, making genetic studies intricate. In about 10% of the cases, the disease is caused by known autosomal genes on three different chromosomes. Genes on chromosomes 1 and 14 have mutations which cause longer forms of amyloid-beta proteins, which readily form plaques. These mutations are associated to early onset cases of the disease. In Down's syndrome the disease seems to be unavoidable. The three copies of chromosome 21 form a surplus of amyloid precursor protein (APP), coded by a gene on this chromosome and leading to Alzheimer symptoms.

Alzheimer's disease thus is genetically heterogeneous and only a small part of the cases are due to identified genes. The causes of late onset cases are probably of many kinds. Some cases are clustered in families; but the risk of first degree relatives is below 50% and monozygous twins have a concordance rate around 60%. About 40% of these patients carry the allele e4 of apolipoprotein E, which increases the risk six-fold. Another allele of this gene, e2, is rare but seems to afford some protection against the disease.

The background is complex also for many other forms of aberrant behaviour and mental illness. When the human genome now is almost totally sequenced and there are possibilities to handle large amounts of data there should be good possibilities to find genes which influence complex non-Mendelian disorders as well as those causing variation within the normal span of measurable characters. Vast numbers of single-nucleotide polymorphisms (SNP-markers) are used in genome wide association studies (GWAS) aimed at finding susceptibility loci, i.e. places on the genome where a sequence difference exist between affected persons and those with normal phenotype. The great expectations so far have not been fulfilled. Indeed, many loci have been found which increase the risk for schizophrenia, depression and other disorders, but they all contribute only a small part of the risk.

The failure of GWASdoes not indicate that the attempt is wrong, only insufficient. The SNPs used are all polymorphisms with common variants. Millions with frequencies below 10% may also be used. Since most detected variants have a low effect and increase the risk by a small amount (1.1–1.5) the power to detect them is small and sample size may have to be increased.

Nor can the simple additive model for gene effects be assumed to be generally prevailing. As is well known in formal genetics genes may suppress or enhance the effects of genes in other parts of the genome and must be assumed important also among variants with quantitative effects.

Further, variations in copy number (CNV) are not included. Historically only large events could be identified by karyotype studies. New micro-array based methods can find much smaller deviations down to a hundred kilobases. Such observations show that repeats and deletions occur everywhere in the genome. Studies of CNVs for associations with diseases as autism and schizophrenia have been made. Deletions and duplications were more common in those affected than in controls but their role as disease drivers is not ascertained (Sebat et al. 2007; Walsh et al. 2008).

Imprinting

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

The epigenetic phenomenon of imprinting has also been indicated to influence behaviour. Among the around 100 known imprinted loci only one allele in the pair is active, the other is silenced and the state is decided by the sex of the gamet-giving parent. It is assumed to be an evolutionary consequence of competing interests of the two parents in how much to invest in the offspring. Igf-2/Igf-2r (insulin-like growth factor 2 and its receptor) is the best studied example. The paternal growth promoting gene is active during foetal life whereas the maternal allele is turned off and this is balanced by reversed activity of the receptor gene.

The Angelman (AS) and Prader–Willi (PWS) syndromes are two neurodevelopmental disorders caused by imbalance of a region in chromosome 15. In AS only the paternal genes are active, in PWS only the maternal. Both diseases develop during infancy, mental retardation occurs but is more pronounced in AS. Marked differences are found in social interactions. The AS child has a happy disposition with positive responses towards mother and other people, in contrast to the PWSchild that gives negative signals, fails to thrive in infancy and later develops a compulsive eating. These differences can be seen as confirming the parental-conflict theory where the paternal genes try to maximize the allocation of maternal resources to the present child whereas the mother's purpose is to moderate the growth in order to save resources for later offspring. In mice imprinting has further been shown to make maternally active genes favour the growth of prefrontal neocortical areas in the brain and paternal genes to favour hypothalamus and those parts of the brain that contributes to emotional and autonomic behaviours.

It is quite clear that the two sexes of a species may have different strategies for survival and reproduction and that different behaviours therefore are favoured. The findings in Turner's syndrome of different influence on social skill for the male and female X-chromosome might widen the usefulness of imprinting to cases where the advantages for sons and daughters differ.

If girls, who normally have two X, are better off with good social skill then this information must come from the father, whose X decides the sex of the child. Skuse et al. (1997) suggested that a gene on the short arm of X escapes inactivation but is turned off on the maternal chromosome. Iwasa et al. (1999) stress the fact that genes on the X-chromosome are selected in a way different from those on autosomes. This can result in the evolution of genomic imprinting opposite to its usual direction. In mice, XO females that have inherited a single X are larger when the X comes from the mother compared to if it is paternal. Since the paternal X normally always goes to daughters this makes sense if the combined maternal plus paternal influence on growth is smaller than a maternal gene alone. Concerning social skill the ability would then be favoured by genes on the paternal X and repressed (perhaps in favour of other capacities) on an imprinted maternal X. Later studies of brain structure and function have been undertaken with X-monosomic females. Enlarged volumes of amygdala grey matter have been found but no impact upon structure. The role of imprinting seems to be more subtle than was first suspected (Skuse 2005).

X-linked imprinted genes, however, may be of importance whenever differences between the sexes are important, and may contribute to the vulnerability of the XYY boys which all have a maternal X. Observations of XXY men, where the extra X may be of maternal or paternal origin, would be of interest.

Imprinting has also been suggested to play a role in autism. A duplication of the chromosome 15 region associated with AS/PWSwas found to give autism when maternally but not paternally inherited (Cook 1997). In GWAS for autism hits have been found to overlap with the imprinted chromosome 15 region.

Badcock and Crespi (2008) have further suggested that autism can be a symptom of imprinting, where biased paternal genes are overexpressed. Autistic individuals have social difficulties, are uninterested in other people and unable to grasp their intentions. As the opposite of this they see paranoia as a maternal bias with delusions of conspiracies, suspecting intentions and personal involvement everywhere. A further indication, they maintain, is that autism is more common in males but more severe in females, whereas depressions and psychoses are more common in females, except for the more severe form, schizophrenia, which usually occurs in males. They interpret this as a threshold difference between the sexes. The higher the threshold the more accentuated the outcome when the shift point is passed.

So far the data are not sufficient and no more than circumstantial evidences exist for these suggestions. Our knowledge of human imprinted genes is incomplete, they are rare and have not been mapped on the human X-chromosome. However, sex-related conflicts and adaptations are real and their genetic foundation in need of explanation.

Brain studies

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

Once a genetic association is established it is necessary to fine map the region more closely to define the cause of phenotypic variation and how the function is altered. It may then be valuable to study in-between events on the road from gene action to behavioural outcome. Autopsies and anatomical studies of the brain can only be performed after death, but the modern techniques of functional magnetic resonance imaging (fMRI) can identify the parts of the brain that are activated in different mental tasks.

Intelligence is a controversial and complex behaviour. It can be separated in different types such as verbal and spatial ability, speed of reaction and memory, and yet all these aspects are correlated. The intelligence quotient, IQ, is an attempt to capture intelligence in one measure. Its heritability is rising up to the age of 15 years, then remaining constant around 0.6 or even rising still higher in old ages (Pedersen et al. 1992). In GWAS, however, SNPs influencing the normal spectrum of verbal ability and IQ have been scarce and account for very little of the variance, at most ¼ of an IQ-point (Butcher et al. 2008).

In tests where cognitive efforts are needed, such as working memory, brain studies have shown that activity is usually restricted to specific regions. Koten et al. (2009) used fMRI to find out if heritability was possible to estimate for brain activity. By using MZ twins and siblings performing a digit span memory test with distraction they could follow brain activity during the different phases of the test: encoding, distraction and recognition. Heritabilities of activation varied among different brain areas and reached values from 0.6 to more than 0.8. Furthermore, the different outcomes in the tests partly depended on a quantitative difference in activation but also on different strategies, giving rise to qualitatively different brain activation patterns.

Neurotransmitter regulation

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References

For signalling between cells across synapses in the brain many different molecules are used as neurotransmitters. The strength of the signal is vital for phenotypic responses. Too little or too much may give rise to aberrant behaviour. Also variations in personality and temperament are associated with signal efficiency. It may therefore be useful to study the activity of neurotransmitters. Their levels can be influenced in different ways: by different activity in the genes responsible of the substance synthesis; by different amounts of receptors on the cells to be activated; by occurrence of regulators that break down the substance; by environmental factors and gene-environment interactions.

Serotonin (5-hydroxytryptamine, 5-HT) is well known to influence emotional moods and anxiety is associated to low levels of serotonin. Several of its regulating systems have been found to be associated with behavioural variations.

Depressions are often treated with anti-depressive drugs such as Prozac that are thought to inhibit the reuptake of serotonin in neuronal synapses and thereby increase the rate of transmission. But some depressed patients fail to respond to this treatment. It has now been found that a single amino acid mutant of the gene tryptophan hydroxylase-2 (Tph 2), that controls serotonin production in the brain lowers this by as much as 80%. The carriers of this mutant have so little serotonin that the usual treatment is without effect (Zhang et al. 2004).

The cause of depression can also be low activity of a serotonin transporting gene. Lesch et al. (1996) found that carriers of one or two copies of a short CNV allele in the promoter region of the 5-H1Tgene in chromosome 17 had reduced serotonin level. The mutant affected behaviour so that its carriers were more easily scared. Later on Hariri et al. (2002) showed that this reaction could be seen more clearly by means of fMRI as a higher activity in the amygdala.

There are 14 different types of serotonin receptors known and each of these interacts with several brain proteins to produce the behavioural effects. Recently one such protein, p 11, has been found in mouse models to activate receptors. Deficiency of p 11 is accompanied by depression-like states in mice and low levels have also been found in post-mortem studies of depressed patients (Svenningson et al. 2006).

Monoamine oxidase A is known to break down neurotransmitters in the brain and has a regulating effect on the serotonin level. The substance is coded by a gene MAOA on the X-chromosome, Aggressive behaviour has been associated with MAOA deficiency in mice studies, and in a Dutch family where a null-allele of the MAOA gene segregated the male carriers all showed antisocial tendencies (Brunner et al. 1993).

The transcription ofthe MAOA-gene is influenced by a stretch of 3–5 repeats of a 30-bp sequence in the promoter region. Shorter variants give less MAOA and more serotonin. A similar repeat sequence has been found in macaques and several ape species (but not in monkeys of the New World) and aggression is associated with the shorter allele. This functional polymorphism thus has been segregating in primates for several millions ofyears and may be an example ofa balancing state where neither allele can outdo the other.

The MAOA-alleles in humans exemplify a case of gene-environmental interaction. Caspi et al. (2002) followed a large group of children in New Zealand from childhood to adolescence. They found that boys mistreated in childhood were more likely to exhibit antisocial behaviour and crime, and especially so if they carried the short allele of MAOA. These boys made up only 12% ofthe group but committed 44% of the crimes. In the absence of abuse, however, those with the short version of the gene were no more antisocial than those with the long allele. The gene frequency in the material was 0.37 for the short allele, so homozygous females should be found, but analyses of the female members of the group were difficult because of phenotypic ambiguities and scarce antisocial events. There was, however, no indication of contrary response. In contrast later studies have shown that in girls, but not in boys, the long MAOA-allele (with higher activity) interacts with unfavourable environment to increase the risk for criminal activity (Sjöberg et al. 2006).

In another study, Caspi et al. (2003) studied the variants of the gene 5-HTT in a New Zealand sample of both sexes to investigate its influence on depression mood. The participants were asked to state number and kind of stressful events that they had experienced between the ages 21 to 26 years, and the question was if such stresses had increased the occurrence of depressions after that age. Among those without stressful events the probability of depression was low and the same regardless of their 5-HTT status. Among those that had experienced one to four such events the negative effects were much stronger for those with two short alleles. 43% had suffered depressions, more than double the proportion among those with two long alleles. Childhood abuse also increased the risk of depression for the homozygous short-allele subjects. Sex seems to play a role also in this context since it has later been indicated that the short allele increases the risk for depression for girls, but the long allele for boys (Sjöberg et al. 2005). If these sex-differences can be confirmed a possible explanation can be hormonal differences or, for MAOA, a dosage difference since the gene is located on the X-chromosome.

Although great improvements are made in characterization of the normal span and aberrations of behaviours it cannot be denied that all behaviours are influenced by the situation in the very moment of action and are not always in accordance with expectations. This gives statistical noise with large variances and makes the outcomes of experiments and personality measurements uncertain. The complexity of thoughts and ideas cannot well be reduced to simple patterns in accordance with fixed diagnostic types. Gene expression networks in the brain are a further difficulty. Networks imply that many different genes are activated simultaneously, interactions that can only be observed in micro-array assays.

During the 20th century we have passed from quantitative estimates of the importance of heredity over significance of karyotypic deviations and inborn errors of metabolism to an appreciation of the complex nature of behaviour. There is no simple linear relation between individual genes and behaviour. In between is the executive organ of the brain, where our actions are shaped from cooperation in genetic networks and experienced environment, where anything from foetal nourishment, over childhood treatment to self-inflicted habits may leave traces.

The glimpses we have got of genetic influences indicate that outcome variations more often are due to regulations of gene expression than to coding differences. Regulation may be accomplished in manifold ways and further steps to understanding will be difficult to achieve. However, more data and improved technology can help, just as serendipitous findings and new ways of thinking.

References

  1. Top of page
  2. Abstract
  3. Heritability
  4. Chromosomal number aberrations
  5. Monogenetic defects
  6. Complex traits
  7. Imprinting
  8. Brain studies
  9. Neurotransmitter regulation
  10. References