Spain S L, Pedroso I, Kadeva N, Miller M B, Iacono W G, McGue M, Stergiakouli E, Davey Smith G, Putallaz M, Lubinski D, Meaburn E L, Plomin R, Simpson M A
Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, King's College London, London, UK.
Department of Psychology, University of Minnesota, Minneapolis, MN, USA.
Mol Psychiatry. 2016 Aug;21(8):1145-51. doi: 10.1038/mp.2015.108. Epub 2015 Aug 4.
Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.
尽管智力（一般认知能力）的个体差异具有高度遗传性，但迄今为止，分子遗传学分析在确定导致其遗传性的特定基因座方面取得的成功有限。本研究首次调查了智力极高个体的外显子变异。在数量遗传模型下，从分布的高端进行抽样应该能增强检测关联的能力。因此，我们对从人群智力分布前0.0003（智商>170）中抽取的1409名个体和3253名未经过选择的基于人群的对照进行了病例对照关联分析。我们的分析集中在Illumina HumanExome BeadChip上检测的假定功能性外显子变异。我们没有观察到任何与智力极高且在整个智力分布范围内可重复关联的个体蛋白质改变变异。此外，在单个基因内未发现多个罕见等位基因的显著关联。然而，使用无关个体之间的全基因组相似性进行的分析（全基因组复杂性状分析）表明，基于易感性模型，基因分型的功能性蛋白质改变变异产生的遗传率估计值为17.4%（标准误1.7%）。此外，对名义上显著关联的调查显示，与智力极高相关的罕见等位基因比在零假设下预期的要少。这一观察结果与罕见功能性等位基因对智力有害而非有益的假设一致。
