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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 (similar to 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.
