Genetic effects influencing risk for major depressive disorder in China and Europe.
Genetic effects influencing risk for major depressive disorder in China and Europe.
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DOI：
10.1038/tp.2016.292
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发表时间：
2017-03-28
影响因子：
6.8
通讯作者：
Kendler KS
中科院分区：
文献类型：
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作者：
Bigdeli TB;Ripke S;Peterson RE;Trzaskowski M;Bacanu SA;Abdellaoui A;Andlauer TF;Beekman AT;Berger K;Blackwood DH;Boomsma DI;Breen G;Buttenschøn HN;Byrne EM;Cichon S;Clarke TK;Couvy-Duchesne B;Craddock N;de Geus EJ;Degenhardt F;Dunn EC;Edwards AC;Fanous AH;Forstner AJ;Frank J;Gill M;Gordon SD;Grabe HJ;Hamilton SP;Hardiman O;Hayward C;Heath AC;Henders AK;Herms S;Hickie IB;Hoffmann P;Homuth G;Hottenga JJ;Ising M;Jansen R;Kloiber S;Knowles JA;Lang M;Li QS;Lucae S;MacIntyre DJ;Madden PA;Martin NG;McGrath PJ;McGuffin P;McIntosh AM;Medland SE;Mehta D;Middeldorp CM;Milaneschi Y;Montgomery GW;Mors O;Müller-Myhsok B;Nauck M;Nyholt DR;Nöthen MM;Owen MJ;Penninx BW;Pergadia ML;Perlis RH;Peyrot WJ;Porteous DJ;Potash JB;Rice JP;Rietschel M;Riley BP;Rivera M;Schoevers R;Schulze TG;Shi J;Shyn SI;Smit JH;Smoller JW;Streit F;Strohmaier J;Teumer A;Treutlein J;Van der Auwera S;van Grootheest G;van Hemert AM;Völzke H;Webb BT;Weissman MM;Wellmann J;Willemsen G;Witt SH;Levinson DF;Lewis CM;Wray NR;Flint J;Sullivan PF;Kendler KS
重度抑郁症（MDD）是一种常见的、复杂的精神疾病，也是世界范围内残疾的主要原因。尽管双胞胎研究表明其适度的遗传性（~30-40%），广泛的异质性和复杂的遗传结构使检测相关遗传风险变体的工作变得复杂。我们结合了来自CONVERGE和PGC MDD研究的单核苷酸多态性（SNP）汇总统计，代表了10 502名中国人（5282例病例和5220名对照）和18 663名欧洲人（9447例病例和9215名对照）。我们确定了表现出一致效应方向的SNPs的比例，评估了多基因风险评分的意义，并估计了MDD在不同祖先中的遗传相关性。随后的跨祖先荟萃分析结合了SNP水平的关联证据。符号测试和多基因得分分析弱支持东亚和欧洲人群之间的SNP效应的重叠。我们估计终生MDD的跨祖先遗传相关性为0.33;仅女性和复发性MDD的估计值分别为0.40和0.41。通过贝叶斯跨祖先荟萃分析（rs 9323497; log 10贝叶斯因子=8.08），GPHN下游的常见变异实现了全基因组显著性，但未能在独立的欧洲样本中复制（P=0.911）。基因集富集分析表明富集的基因参与神经元发育和轴突运输。我们成功地证明了在东亚和欧洲人群中MDD的部分共享多基因基础。总之，这些发现支持MDD的复杂病因学和易感遗传因素的可能人群差异，对未来的遗传研究具有重要意义。
Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30–40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.