Nature vs Nurture; the effect of genetics on personality

By Nitya Gupta

Since the early 90s, studies have observed that identical twins (that share the same DNA), when raised apart, in separate households by different parents, have incredibly similar personalities. This equivalence is observed to a lesser extent between fraternal twins (whose DNA though similar, are not identical), providing compelling evidence that there is a genetic aspect to our behaviour and personality (Tellegen et al., 1988). 

Personality is defined as the relatively enduring patterns of thought, feeling, and behavior that reflect the tendencies to respond in a particular manner under certain circumstances. The Five Factor model categorises personality under 5 higher order traits; neuroticism, extraversion, conscientiousness, agreeableness and openness to experience (Sanchez-Roige et al., 2018).

The genetic influence on personality was quantified and determined to be in the range of  40-50% (Dagher et al., 2009). Yet, the precise genetic foundation of these traits from a molecular perspective is incredibly complex and largely elusive. This is because it’s impossible to pinpoint a gene as, for example an organized or anxiety gene, as these characteristics are determined by the combined effect of a multitude of genes.

Pioneers in the field identified a correlation between the ‘novelty-seeking’ personality trait and the dopamine D4 receptor gene (D4DR). At lunchtime in a foreign country, people who are ‘novelty-seeking’ would rather eat an exotic local delicacy, whereas people who aren’t may prefer to eat at a familiar restaurant. Dopamine is a neurotransmitter released in the ‘reward centre’ of the brain to motivate beneficial activities such as drinking water, that generates a feeling of pleasure, well-being and increased alertness. The D4DR gene contains a 48 nucleotide long, variable number of tandem repeat (VNTR) polymorphism on exon III, that is typically repeated 5 times, however, the number of repeats can be as low as 2 or as frequent as 11. The longer this sequence of repeats, the less effective the receptor is at binding dopamine. Individuals with low responsiveness to dopamine were identified as more likely to be easily bored, and were reported to have a more thrill-seeking and adventurous personality. While those with an increased sensitivity, and shorter D4DR genes lack motivation and initiative, and receive enough ‘reward’ from simple tasks. The DRD4 VNTR polymorphism was predicted to account for 4% of the variation related to novelty seeking (Ebstein et al., 1996; Benjamin et al, 1996).

While multiple studies have been able to reproduce these findings, others have not (Munafò et al., 2008; Smillie et al., 2010; Kazantseva et al., 2011). Subsequent meta-analysis reports, in which results from multiple studies are combined and analyzed, remain inconclusive and uncertain of any correlation. However, a recent study reported evidence of the correlation between DRD4 VNTR polymorphism and novelty-seeking (He et al., 2018).

The research described above follows the candidate gene approach in which a hypothesis relating a gene to a personality trait is formulated, based on physiological or psychopharmacological studies. This is subsequently tested by having participants fill out personality questionnaires and observing the gene in question in their DNA to check if a particular variation of that gene can be associated with the hypothesized trait. In this approach, genes are selected largely due to their involvement in neurotransmitter systems. An example is the suspected correlation between a genetic variation on the serotonin transporter gene and anxiety. This was hypothesized due to the majority of psychopharmaceuticals (prescribed to treat anxiety) being ‘selective serotonin reuptake inhibitors’, that block the serotonin transporters to increase serotonin levels between neurons. However, attempts to reproduce these results using the candidate gene approach are often only partially successful, and therefore often categorised as false positives (Montag et al., 2020).

A genome-wide association study (GWAS) is a modern approach that does not implement any theoretical guidance when associating specific genetic variations with phenotypic personality traits. Instead, the genomes of multiple individuals are scanned simultaneously, and genetic variations and SNPs that could be associated with particular traits are identified based on commonalities between the individuals’ genomes and their personalities (Montag et al., 2020).

The earliest GWAS for personality had 1,000–5,000 participants, which proved to be underpowered and failed to yield significant results. It was not until the release of the genetic data from the UK Biobank that sufficiently large samples became available and dramatically boosted the ability to detect significant variants. For instance, Nagel et al., 2018 identified 136 significant loci (fixed regions on chromosomes) implicating 599 genes associated with neuroticism using a sample size of 449,484. 

Almost all hits from a GWAS are variants in non-coding and intergenic regions; these variants may be involved in gene regulation or linkage disequilibrium (a situation in which variants are co-inherited due to their genomic proximity) with functional variants affecting personality. To conclusively ensure that only functional variants are collected, the results are corrected for multiple testing, and a follow-up candidate gene approach is carried out. In this way, GWAS essentially produces a list of candidates to be further investigated by the candidate gene approach, thereby combining both methods (Montag et al., 2020).

Information provided by GWAS enables clustering of variants into biochemical, dopaminergic or oxytocinergic pathways, which allows for an analysis of how strongly a chemical pathway influences a particular psychological trait. The use of GWAS has allowed the identification of genetic correlations between the big five personality traits, and between traits and psychiatric disorders. Neuroticism has been correlated with anxiety disorders, major depression, attention deficit hyper-activity disorder (ADHD), anorexia nervosa, and schizophrenia and negatively correlated with subjective well-being, and even IQ and educational attainment (Montag et al., 2020).

Genetic variation affects molecular, cellular, and eventually system-level pathways that then result in a certain trait. Thus, it is highly plausible that theoretically related phenotypes that rely on a shared neural resource are also genetically associated. Unlike GWAS that searches for statistical associations between one phenotype and millions of genetic variants, phenome wide association studies (PheWAS) are designed to assess statistical associations between a single variant and several phenotypic personality traits – this can reveal insights into genetic associations beyond GWAS (Denny et al., 2013).

Intelligence is the ability to learn, reason and solve problems and has been found to be highly heritable and even predict educational, occupational and health outcomes. Recent GWAS studies have successfully identified inherited genome sequence differences that account for 20% of the 50% heritability of intelligence (Plomin., 2018).

Even though people are born with certain genetic predispositions, personalities are also heavily environmentally influenced and socially determined, and certain social influences such as trauma can even switch specific genes on and off. Parents can still make huge impacts in their children’s lives by encouraging shy kids to speak up for instance. Moreover, research in this field is highly relevant from a clinical perspective towards preventing, diagnosing and treating psychogenetic pathological conditions and mental illnesses such as depression and bipolar disorder (Ridley., 2000).

References:

Benjamin, J., Li, L., Patterson, C., Greenberg, B.D., Murphy, D.L. & Hamer, D.H. 1996, “Population and familial association between the D4 dopamine receptor gene and measures of Novelty Seeking”, Nature genetics, vol. 12, no. 1, pp. 81-84.

Dagher, A. & Robbins, T.W. 2009, “Personality, Addiction, Dopamine: Insights from Parkinson’s Disease”, Neuron (Cambridge, Mass.), vol. 61, no. 4, pp. 502-510.

Denny, J.C., Bastarache, L., Ritchie, M.D., Carroll, R.J., Zink, R., Mosley, J.D., Field, J.R., Pulley, J.M., Ramirez, A.H., Bowton, E., Basford, M.A., Carrell, D.S., Peissig, P.L., Kho, A.N., Pacheco, J.A., Rasmussen, L.V., Crosslin, D.R., Crane, P.K., Pathak, J., Bielinski, S.J., Pendergrass, S.A., Xu, H., Hindorff, L.A., Li, R., Manolio, T.A., Chute, C.G., Chisholm, R.L., Larson, E.B., Jarvik, G.P., Brilliant, M.H., McCarty, C.A., Kullo, I.J., Haines, J.L., Crawford, D.C., Masys, D.R. & Roden, D.M. 2013, “Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data”, Nature biotechnology, vol. 31, no. 12, pp. 1102-1111.

Ebstein, R.P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., Bennett, E.R., Nemanov, L., Katz, M. & Belmaker, R.H. 1996, “Dopamine D4 receptor (D4DR) exon III polymorphism associated with the human personality trait of Novelty Seeking”, Nature Genetics, vol. 12, no. 1, pp. 78-80.

He, Y., Martin, N., Zhu, G. & Liu, Y. 2018, “Candidate genes for novelty-seeking: a meta-analysis of association studies of DRD4 exon III and COMT Val158Met”, Psychiatric Genetics, vol. 28, no. 6, pp. 97-109.

Kazantseva, A., Gaysina, D., Malykh, S. & Khusnutdinova, E. 2011, “The role of dopamine transporter (SLC6A3) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms in personality traits”, Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 35, no. 4, pp. 1033-1040.

Montag, C., Ebstein, R.P., Markett, S. & Jawinski, P. 2020, “Molecular genetics in psychology and personality neuroscience: On candidate genes, genome wide scans, and new research strategies”, Neuroscience & Biobehavioral Reviews, vol. 118, pp. 163-174.

Munafò, M.R., Yalcin, B., Willis-Owen, S.A. & Flint, J. 2008, “Association of the Dopamine D4 Receptor (DRD4) Gene and Approach-Related Personality Traits: Meta-Analysis and New Data”, Biological Psychiatry, vol. 63, no. 2, pp. 197-206.

Plomin, R. & von Stumm, S. 2018, “The new genetics of intelligence”, Nature Reviews. Genetics, vol. 19, no. 3, pp. 148-159.

Reist, C., Ozdemir, V., Wang, E., Hashemzadeh, M., Mee, S. & Moyzis, R. 2007, “Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in Asians: Haplotype characterization and relevance of the 2-repeat allele”, American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, vol. 144B, no. 4, pp. 453-457.

Ridley, M. 2000, “Personality” in Genome: The Autobiography of a Species In 23 Chapters HarperCollins Publishers, New York, pp. 161-172.

Sanchez-Roige, S., Gray, J.C., MacKillop, J.K., Chen, C. & Palmer, A.A. 2018, “The genetics of human personality”, Genes, brain, and behavior, vol. 17, no. 3, pp. e12439.

Smillie, L.D., Cooper, A.J., Proitsi, P., Powell, J.F. & Pickering, A.D. 2010, “Variation in DRD2 dopamine gene predicts Extraverted personality”, Neuroscience letters, vol. 468, no. 3, pp. 234-237.

Tellegen, A., Lykken, D.T., Bouchard, T.J., Wilcox, K.J., Segal, N.L. & Rich, S. 1988, “Personality similarity in twins reared apart and together”, Journal of Personality and Social Psychology, vol. 54, no. 6, pp. 1031-1039.

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