Basic Research in Personality: Molecular Genetics of Personality

去年，为了探索人格的遗传结构，我们在6,148名撒丁岛人的样本中研究了NEO-PI-R结构域和方面特征的遗传性。在所有35个领域和方面，遗传效应解释了19%的方差，从9.4%的可接受性方面的温柔-体贴到32.8%的经验开放性。这清楚地表明了实况调查团各方面的遗传和生物组成部分。 对性状的分子遗传基础的研究已经从候选基因研究发展而来 到更有前途的全基因组关联扫描或GWA扫描。最近使用GWA扫描的研究可靠地确定了与复杂性状和疾病相关的新的常见变异，包括BMI，身高，炎症性肠病以及1型和2型糖尿病。为了识别与人格的五个维度和30个方面中的每一个相关的SNP，我们对来自撒丁岛遗传隔离人群的3，972名个体进行了GWA扫描。我们正在测试通过质量控制的362，129个单核苷酸多态性或SNP（控制年龄，年龄平方，性别和家庭结构）的关联。关联分析是针对人格量表的所有因素和方面进行的，即修订的NEO人格量表（NEO-PI-R）。由于大量的比较伴随着α膨胀，我们只关注那些比背景信号更强的结果，这些结果通常小于E-5或-6。初步结果鼓励我们检查几个强信号，一些在以前与大脑功能或精神疾病有关的基因内或附近（例如，SNAP-25、DYRK1A、CLOCK、CDH13、CDH23、BDNF、CNTNAP 2、CTNNA 2、IKBKAP）。 其中，特别有趣的是神经质与SNAP-25基因的关联，该基因在神经递质释放，轴突生长和突触可塑性中起着关键作用。在Coloboma小鼠中缺失含有SNAP-25基因的区域会导致神经异常，包括多动症。这种表型与SNAP 25在注意缺陷多动障碍中的作用一致，这已经在许多研究中进行了测试，大多数结果是阳性的。此外，SNAP 25水平的异常与其他精神疾病有关。除了对人格特质的内在兴趣之外，SNAP-25和神经质之间的关联与神经质是中间表型/内表型的几种精神疾病有关。 在外倾性和靠近脑源性神经营养因子（BDNF）基因的SNP之间发现了更有趣的关联。特别是，外倾性与广泛研究的Val 66 Met变体（rs6265）相关。BDNF支持现有神经元的存活以及新神经元和突触的生长和分化。

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.