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

Genetic Effects Influencing Risk for Major Depressive Disorder in China and Europe

T B Bigdeli  1 S Ripke  2   3   4 R E Peterson  1 M Trzaskowski  5   6 S-A Bacanu  1 A Abdellaoui  7 T F M Andlauer  8   9 A T F Beekman  10 K Berger  11 D H R Blackwood  12 D I Boomsma  7 G Breen  13   14 H N Buttenschøn  15 E M Byrne  6 S Cichon  16   17   18   19 T-K Clarke  12 B Couvy-Duchesne  6   20   21 N Craddock  22 E J C de Geus  7   23 F Degenhardt  19   24 E C Dunn  25   26   27 A C Edwards  1 A H Fanous  28 A J Forstner  19   24 J Frank  29 M Gill  30 S D Gordon  20 H J Grabe  31 S P Hamilton  32 O Hardiman  33 C Hayward  34 A C Heath  35 A K Henders  6 S Herms  19   24   36 I B Hickie  37 P Hoffmann  19   24   38 G Homuth  39 J-J Hottenga  7 M Ising  40 R Jansen  10 S Kloiber  40 J A Knowles  41 M Lang  29 Q S Li  42 S Lucae  40 D J MacIntyre  12 P A F Madden  35 N G Martin  20   43 P J McGrath  44 P McGuffin  14 A M McIntosh  12   45 S E Medland  20 D Mehta  6 C M Middeldorp  7 Y Milaneschi  10 G W Montgomery  46 O Mors  47 B Müller-Myhsok  8   9   48 M Nauck  49 D R Nyholt  50 M M Nöthen  19   24 M J Owen  51 B W J H Penninx  10 M L Pergadia  52 R H Perlis  53   26 W J Peyrot  10 D J Porteous  54 J B Potash  55 J P Rice  56 M Rietschel  29 B P Riley  1   57 M Rivera  58   14 R Schoevers  59 T G Schulze  29   60   61   62   63 J Shi  64 S I Shyn  65 J H Smit  10 J W Smoller  25   26   27 F Streit  29 J Strohmaier  29 A Teumer  66 J Treutlein  29 S Van der Auwera  31 G van Grootheest  10 A M van Hemert  67 H Völzke  66 B T Webb  1 M M Weissman  68   69 J Wellmann  11 G Willemsen  7 S H Witt  29 D F Levinson  70 C M Lewis  14   71 N R Wray  5   6 J Flint  72   73 P F Sullivan  74   75   76 K S Kendler  1   57
Affiliations
Free PMC article

Genetic Effects Influencing Risk for Major Depressive Disorder in China and Europe

T B Bigdeli et al. Transl Psychiatry. .
Free PMC article

Abstract

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.

Conflict of interest statement

PFS is a scientific advisor to Pfizer. HJG reports receiving funding from the following: German Research Foundation; Federal Ministry of Education and Research Germany; speakers honoraria from, Eli Lilly and Servier. BM-M consulted for Affectis Pharmaceuticals. RP has received consulting fees from Proteus Biomedical, Concordant Rater Systems, Genomind and RID Ventures. The remaining author declare no conflict of interest.

Figures

Figure 1
Figure 1
Trans-ancestry association of polygenic risk scores with major depressive disorder. For scores based on results from PGC or CONVERGE, the variance in risk explained in the other study is shown on the y axis in terms of Nagelkerke's pseudo-R2; scores based on various P-value inclusion thresholds are displayed as shaded bars. CONVERGE, China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology; MDD, major depressive disorder; PGC, Psychiatric Genomics Consortium.

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