GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.
GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.
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DOI：
10.1038/mp.2016.244
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发表时间：
2017-03
影响因子：
11
通讯作者：
Lencz T
中科院分区：
文献类型：
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作者：
Trampush JW;Yang ML;Yu J;Knowles E;Davies G;Liewald DC;Starr JM;Djurovic S;Melle I;Sundet K;Christoforou A;Reinvang I;DeRosse P;Lundervold AJ;Steen VM;Espeseth T;Räikkönen K;Widen E;Palotie A;Eriksson JG;Giegling I;Konte B;Roussos P;Giakoumaki S;Burdick KE;Payton A;Ollier W;Horan M;Chiba-Falek O;Attix DK;Need AC;Cirulli ET;Voineskos AN;Stefanis NC;Avramopoulos D;Hatzimanolis A;Arking DE;Smyrnis N;Bilder RM;Freimer NA;Cannon TD;London E;Poldrack RA;Sabb FW;Congdon E;Conley ED;Scult MA;Dickinson D;Straub RE;Donohoe G;Morris D;Corvin A;Gill M;Hariri AR;Weinberger DR;Pendleton N;Bitsios P;Rujescu D;Lahti J;Le Hellard S;Keller MC;Andreassen OA;Deary IJ;Glahn DC;Malhotra AK;Lencz T
人类认知的复杂性导致认知基因组学在使用全基因组关联研究（GWAS）方法进行基因发现方面落后于许多其他领域。为了克服这些障碍，目前的研究利用GWAS荟萃分析来检查常见遗传变异（~ 8 M单核苷酸多态性（SNP），次要等位基因频率<1%）与认知基因组学联盟（COGENT）24个队列中35298名欧洲血统健康个体样本中一般认知功能的相关性。此外，我们利用单个SNP查找和多基因评分分析来确定与其他相关神经行为表型的遗传重叠。我们的主要GWAS荟萃分析确定了两个新的SNP位点（最高SNP：2号染色体上CENPO基因的rs76114856和1号染色体上LOC 105378853附近的rs6669072）与全基因组显著性水平（P<5 × 10−8）的认知表现相关。基于基因的分析在染色体17q21.31、17p13.1和1p13.3处确定了另外三个Bonferroni校正的显著位点。总的来说，基因组中常见的变异导致保守估计的SNP遗传率为21.5%（s.e.= 21.5%）。0.01%）的一般认知功能。与先前的GWAS的认知表现和教育程度的整合产生了几个额外的显着位点。最后，我们发现认知能力与教育程度、几种精神疾病、出生身长/体重和吸烟行为之间存在强有力的多基因相关性，以及与开放性人格特质之间的一种新的遗传关联。这些数据为神经认知功能的遗传学提供了新的见解，有助于理解神经精神疾病的病理生理学。
The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.