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Genetic effects influencing risk for major depressive disorder in China and Europe

Transl Psychiatry. 2017 Mar 28;7(3):e1074. doi: 10.1038/tp.2016.292.

Authors/Editors: 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.
Publication Date: 2017



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.

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