Study of complex traits:Genetics of Personality as a model

Naeim Ehtesham

Supervisor: Dr. Kheirollahi

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Studies in personality

• Large portion of the variation in behavior can be captured by a relatively small number

of core dimensions

• Five Factor Model (FFM) of personality

• cross-cultural universals

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cont…

• John, O. P.; Srivastava, S. The Big Five Trait Taxonomy: In Handbook of Personality: Theory and

Research, 2nd ed1999; pp 102–138.4

cont…

• Personality is strong predictor of important life outcomes as social class

• Differences in mental health

• Academic and social achievement

• Quality of our relationships with romantic partners, relatives and friends

• …

• Resolving genetic basis of personality will be key to resolving genetic basis of some

mental disorders

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Twin Studies

• Major evidence in support of a heritable basis comes from the comparison of the

similarity of (MZ) and (DZ) twins

• If we assume that:

(1) MZ twins are no more likely than DZ twins to share trait-relevant environmental

influences

(2) There is no assortative mating for personality

(3) All relevant genetic effects are additive

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cont…

• Expected correlation for reared-together MZ (rMZT) and DZ (rDZT) along with the total

trait variance (normed to 1.0) can be expressed as:

• rMZT =a2+c2

• rDZT = 1

2𝑎2+c2

• 1.0 = a2+c2+e2

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Falconer or ACE

model

a2 = 2(rMZT − rDZT)

c2 = 2rDZT − rMZT

e2 = 1.0 − rMZT

cont…

Bouchard, T. J. The Genetics of Personality. In Handbook of Psychiatric Genetics; 2011; pp

273–296

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cont…

• Validity of the MZ–DZ comparison rests on two fundamental assumptions:

(1) Personalities of twins do not differ from those of non-twins

(2) MZ are no more likely than DZ to share trait-relevant environmental influences

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cont…

• No evidence that personalities of twins differ systematically from that of singletons

• Supporting generalizability of findings from twin studies to the larger non-twin

population

• Latter assumption has received substantial attention in the empirical literature, with the

consistent finding that greater MZ than DZ similarity in personality cannot be attributed

to differential treatment (e.g. by parents)

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cont…

• Strongest evidence against the hypothesis that differential environmental similarity can account for reared-together MZ–DZ differences in personality similarity is studies on reared-apart twins

Pedersen Neuroticism, Extraversion, and Related Traits in Adult Twins Reared Apart and Reared Together. J. Soc. Pers. Psychol. 1998, 55, 950–957

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Adoption Studies

• Computation weighted-average adoptive sibling (i.e. nonbiologically related siblings

who are reared together) correlation for the five basic dimensions of personality

• Extraversion= 0.07 neuroticism= 0.11 agreeableness= o.o6

• Little or no personality similarity among adoptive relatives

• Little personality resemblance between adoptive parents and the nongenetically related

offspring they rear

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cont…

• It is informative to compare personality resemblance of adoptive relatives with that for

first-degree biological relatives

• Average adoptive parent-adopted child personality correlation of 0.01

• Average biological parent-adopted child personality correlation of 0.3

• First-degree biological relatives appear to show more similarity in personality than

adoptive relatives

• Confirming that growing up in the same home has little impact on personality similarity

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Search for genes that influence personality

• Candidate Gene Approaches

• Genome-Wide Strategies

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Candidate Gene Approaches

• Biological basis of differences in personality had been hypothesized to be due to

differences in brain neurotransmission systems

• Dopaminergic system- target for study of personality traits such as impulsivity and

sensation seeking

• Serotonin system- neuroticism and anxiety-related personality characteristics

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cont…

• DRD4 VNTR polymorphism - sensation seeking

• Polymorphism in SLC6A4 - neuroticism

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cont…

• In an attempt to circumvent the problems inherent to small sample studies, geneticists have increasingly turned to meta-analysis

Munafo, M. R.; Flint, J. Meta-Analysis of Genetic Association Studies. Trends Genet. 2004, 20 (9), 439–444

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cont…

• This failure might be due to:

• Differences in the genetic bases of traits in different populations

• The small size of the effects of any single gene

• Choice of the wrong candidates

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Genome-Wide Strategies

• Does not require any hypotheses about which genes are related to the trait

• P-value threshold set to p < 5 × 10-8

• Most highly associated snps in these studies failed to meet the stringent significance

threshold of p < 5 × 10-8, but several were marginally significant

• GWAS are efficient and successful methods when some genes have relatively large

effects that stand out from the distribution of random effects, as is the case with some

diseases

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Strategies to increase sensitivity of genetic studies

of personality

• Genetic Scores

• The Endophenotype Approach

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Genetic Scores

• Small effect associated with any specific individual genetic variant

• The most common strategy for dealing with the problem of false positives is to choose a

small number of snps with the largest associations with the phenotype at different p-value

thresholds and determine if they are significantly associated with the phenotype in a

second, independent replication sample

• Researchers need know Nothing about why a given item (or SNP) is associated with the

trait; they only require data showing that it is

• In essence, this is a version of the candidate gene approach, in which the candidate SNPs

are selected empirically rather than theoretically

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The Endophenotype Approach

• Personality characteristics are clearly far removed from the primary function of DNA

• Resolving the genetics of complex phenotypes

• Indirectly, by first resolving the genetics of relevant intermediate or endophenotypes

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cont…

• Effect of specific genetic variants may be stronger, and thus easier to identify, for

endophenotypes than for observed behavior because the former are more proximal to the

primary gene product than the latter

• Developments in imaging technology have allowed neuroscientists to learn much about

the neurological basis and providing a rich source of potential endophenotypes

• Combination of genetic and neuroimaging approaches holds great potential for

unraveling the genetics of complex behavioral systems like personality

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Gene–environment interplay

• Fundamental differences that exist between human behavior and other heritable human

phenotypes

• Environments are not distributed at random but rather are a reflection in part of an

individual’s own behavior

• An easygoing, affable individual will experience a much different social environment

than a tense, surly individual

• Genetic effects on personality are almost certain to depend on environmental exposure

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Passive gene environment correlation

Among biologically related relatives (i.e., Nonadoptive families), parents provide not only

their children’s genotypes but also their rearing environment. Therefore, the child’s

genotype and home environment are correlated

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Evocative gene-environment correlation

• Individuals’ genotypes influence the responses they receive from others

• Child who is predisposed to having an outgoing, cheerful disposition might be more

likely to receive positive attention from others than a child who is predisposed to timidity

and tears

• Kids acting up may provoke negative reactions from their parents

• Evocative gene environment correlation can influence the way an individual experiences

the world

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Active gene-environment correlation

• An individual actively selects certain environments and takes away different things from

his/her environment

• These processes are influenced by an individual’s genotype

• Individual predisposed to high sensation seeking may be more prone to attend parties and

meet new people, thereby actively influencing the environments he/she experiences

• According to this view, people’s experiences are the immediate shapers of their

personalities, but their experiences reflect their genes, via the influence of the latter on

the development of their emotional and motivational systems

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Difficulty to determine whether the genes or the environment is

the causal agent

• So often genetic and environmental influences do not represent independent sources of influence

• Individuals are genetically predisposed toward sensation seeking, and this makes them more likely to spend time in bars (a gene-environment correlation), and this increases their risk for alcohol problems, are the predisposing sensation-seeking genes or the bar environment the causal agent?

• In actuality, the question is moot—they both played a role

• It is much more informative to try to understand the pathways of risk than to ask whether the genes or the environment was the critical factor

• Genetic and environmental influences are intertwined

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Methods for studying gene-environment interaction

• Animal Research

• Adoption studies

• Twin studies

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Animal research

• The most straightforward method for detecting gene-environment interaction

• Different genetic strains of animals can be subjected to different environments to directly

test for gene-environment interaction

• Rats were selectively bred to perform differently in a maze-running experiment under

standard environmental conditions

• Maze bright & maze dull

• An enriched condition

• A restricted condition

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Cont…

• Mammalian species, it is now known that there are genetic factors underlying variation in

reactivity –(tendency to become emotionally aroused and fearful)

• Reactive animals appear jittery and hesitate to explore novel environments

• In rhesus monkeys, a gene has been isolated one of whose alleles is associated with the

emergence of a reactive temperament

• young animals carrying the ‘‘reactive’’ allele are particularly vulnerable to variations in

early rearing experience

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Cont…

• If they are subjected to maternal deprivation during their first six months (reared with

peers but no adult females) ,they display a variety of pathological symptoms into

adulthood, including incompetence in social interactions, low status in peer groups, and

incompetence in mothering their own offspring

• Young animals who do not carry the genetic risk factor are much less affected by

maternal deprivation

• Genetically reactive newborn monkeys are being cross-fostered to nonreactive mothers,

and indicate that calm mothering does indeed buffer them from the development of

strongly reactive behavior

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Adoption studies

• Adopted children whose biological parents have a history of criminality

• Among adoptees who carried a risk factor from their biological parents, those who had

been adopted into dysfunctional homes (a disturbed environment, as defined by

psychopathology, divorce, or legal problems among the adoptive parents) were over

three times more likely to become criminals

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Twin studies

• Religiosity was shown to moderate genetic influences on alcohol use initiation

• Influences on antisocial behavior were higher in the presence of:

• Delinquent peers

• High parental negativity

• Low parental warmth

• High paternal punitive discipline

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• MAOA gene is located on the X . it encodes the MAOA

enzyme, which metabolizes norepinephrine (NE), serotonin

(5-HT), and dopamine (DA), rendering them inactive

• Increased aggression and increased levels of brain NE, 5-

HT, and DA were observed in mouse line in which the

gene encoding MAOA was deleted and aggression was

normalized by restoring MAOA expression

• 1,037 children has been assessed at ages 3, 5, 7, 9, 11, 13,

15, 18-symptoms of antisocial personality disorder were

ascertained at age 26 by collecting information about the

study members from people they nominated as

"someone who knows you well."

• Effect of childhood maltreatment on antisocial behavior

was significantly weaker among males with high MAOA

activity than among males with low MAOA activity

• Males with the low-maoa activity genotype who were

maltreated in childhood had significantly elevated

antisocial scores relative to their low-maoa counterparts

who were not maltreated

• Males with high MAOA activity did not have elevated

antisocial scores, even when they had experienced

childhood maltreatment

• A well-characterized variable number tandem repeat

(VNTR) polymorphism exists at the promoter of the

MAOA gene, which is known to affect expression

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Epigenetics: a potential biological mechanism for gene environment

interaction

• What are the biological processes by which exposure to environmental events could

affect outcome?

• Animal studies have yielded compelling evidence that early environmental manipulations

can be associated with long-term effects that persist into adulthood

• Maternal licking in rats is known to have long-term influences on stress response in

their offspring

• These findings parallel research in humans that suggests that early life experiences can

have long-term effects on child development

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Cont…

• Evaluating epigenetic changes in humans is more difficult because epigenetic marks can

be tissue specific

• Access to human brain tissue is limited to postmortem studies of donated brains

• Recent study of human brain samples from the Quebec suicide brain bank

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• Albert H.C. Phenotypic differences in genetically identical organisms: the epigenetic perspective, Human Molecular Genetics,2005

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CONCLUSION

• Early twin and adoption studies documented the importance of genetic influences

• Major goal of genetic analysis is now to identify the specific genes that influence

personality and determine how the effects of those genes interact with and are modulated

by experience

• As with any complex phenotype, we can expect that progress in mapping genes for

personality will be slow and subject to false leads

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CONCLUSION

• By studying normal personality, we want to identify candidate genes for psychiatric

disorders

• If appropriate candidate genes can be discovered, the ultimate goal is to develop drugs

that act on specific targets.

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