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

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.

Polygenic risk for severe psychopathology among Europeans is associated with major depressive disorder in Han Chinese women

“…For comparison, however, the trans-ethnic correlation for recurrent MDD is 0.41 (Bigdeli et al 2017), thus the magnitudes of our observed correlations are not unexpected. Findings for the non-melancholic MDD subtype further support the hypothesis that genetic factors are common across more severe psychopathologies.…”

“… a Within-PGC results obtained from Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) b Within-PGC results obtained from Cross-Disorder Group of the Psychiatric Genomics Consortium et al (2013) c PGC–CONVERGE results obtained from Bigdeli et al (2017) …”

<b><i>VRK2</i></b>, a Candidate Gene for Psychiatric and Neurological Disorders

“…MDD also shows substantial heritability (approx. 0.37) [9, 10] and polygenic inheritance [11, 12]. However, promis ing genetic risk candidates for SCZ and MDD had not been well implicated until the emergence of recent large-scale genome-wide association studies (GWAS) [13-21].…”

Genome-wide association study of depressive symptoms in the Hispanic Community Health Study/Study of Latinos

“…However, there was generally only modest support for shared genetic effects between Hispanics/Latinos and European Americans as shown in the analyses examining more SNPs or aggregate polygenic variation as measured through a genetic risk score. Prior trans-ethnic analyses of MDD have also suggested possible population differences in genetic liability to depression across racial/ethnic groups (Bigdeli et al, 2017). The lack of observed overlap in genetic risk factors for depression across ancestry groups could be due to low power in our sample.…”