Basic Research in Personality: Molecular Genetics of Personality

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Last year in an effort to explore the genetic architecture of personality, we examined the heritability of NEO-PI-R domain and facet traits in a sample of 6,148 Sardinians. Across all 35 domains and facets, genetic effects explained 19% of the variance, ranging from 9.4% for the Agreeableness facet Tender-Mindedness to 32.8% for Openness to Experience. This demonstrates clearly a genetic, biological component to the FFM dimensions. The search for the molecular genetic basis of traits has evolved from candidate gene studies to the more promising genome wide association scans or GWA scans. Recent studies that used GWA scans have reliably identified new common variants associated with complex traits and diseases that include BMI, height, inflammatory bowel disease, and type 1 and type 2 diabetes. To identify SNPs associated with each of the five dimensions and 30 facets of personality we performed a GWA scan of 3,972 individuals from a genetically isolated population within Sardinia. We are testing for the association of 362,129 single nucleotide polymorphisms or SNPs (Controlling for age, age-squared, gender and family structure) that passed quality control. The association analyses are performed for all factors and facets of the personality inventory, the Revised NEO Personality Inventory (NEO-PI-R. Because of the alpha inflation accompanying the huge numbers of comparisons, we focus only on those results that are stronger than the background signals usually o values less than E-5 or -6. Preliminary results encourage us to examining several strong signals, some within or near genes previously implicated in brain functions or psychiatric disorders (e.g., SNAP-25, DYRK1A, CLOCK, CDH13, CDH23, BDNF, CNTNAP2, CTNNA2, IKBKAP). Among these, particularly interesting is the association of Neuroticism with the SNAP-25 gene, which plays a critical role in neurotransmitter release, axonal growth, and synaptic plasticity. Deletion of the region containing the SNAP-25 gene in the Coloboma mouse causes neurological abnormalities, including hyperactivity. Such a phenotype is consistent with a role for SNAP25 in attention deficit hyperactivity disorder, which has been tested in a number of studies with mostly positive results. Furthermore, abnormalities in the level of SNAP25 have been linked to other psychiatric disorders. In addition to its intrinsic interest for a personality trait, the association between SNAP-25 and Neuroticism is relevant to several psychiatric disorders for which Neuroticism is an intermediate phenotype/endophenotype. A further interesting association is found between Extraversion and SNPs lying close to the brain-derived neurotrophic factor (BDNF) gene. In particular, Extraversion was associated with the extensively studied Val66Met variant (rs6265). BDNF supports the survival of existing neurons and the growth and differentiation of new neurons and synapses.