What is the genetic architecture of recurrent major depressive disorder (MDD) in Han Chinese women?
In this case-control study of MDD, aggregate genetic risk accounted for 21.4% of the variance in MDD liability with significant heritability found across chromosomes and the allelic spectrum. Enrichment of variant associations was seen in protein-coding regions, 3′ UTR, and DNase I-hypersensitive sites, as was significant burden of singleton exonic variants in MDD, particularly in genes expressed in the brain or with mitochondrial gene products.
Results confirm a complex genetic architecture for MDD, supporting etiological mechanisms for both common and rare genetic variation to MDD risk.
Despite the moderate, well-demonstrated heritability of major depressive disorder (MDD), there has been limited success in identifying replicable genetic risk loci, suggesting a complex genetic architecture. Research is needed to quantify the relative contribution of classes of genetic variation across the genome to inform future genetic studies of MDD.
To apply aggregate genetic risk methods to clarify the genetic architecture of MDD by estimating and partitioning heritability by chromosome, minor allele frequency, and functional annotations and to test for enrichment of rare deleterious variants.
Design, Setting, and Participants
The CONVERGE (China, Oxford, and Virginia Commonwealth University Experimental Research on Genetic Epidemiology) study collected data on 5278 patients with recurrent MDD from 58 provincial mental health centers and psychiatric departments of general medical hospitals in 45 cities and 23 provinces of China. Screened controls (n = 5196) were recruited from a range of locations, including general hospitals and local community centers. Data were collected from August 1, 2008, to October 31, 2012.
Main Outcomes and Measures
Genetic risk for liability to recurrent MDD was partitioned using sparse whole-genome sequencing.
In aggregate, common single-nucleotide polymorphisms (SNPs) explained between 20% and 29% of the variance in MDD risk, and the heritability in MDD explained by each chromosome was proportional to its length (r = 0.680; P = .0003), supporting a common polygenic etiology. Partitioning heritability by minor allele frequency indicated that the variance explained was distributed across the allelic frequency spectrum, although relatively common SNPs accounted for a disproportionate fraction of risk. Partitioning by genic annotation indicated a greater contribution of SNPs in protein-coding regions and within 3′-UTR regions of genes. Enrichment of SNPs associated with DNase I-hypersensitive sites was also found in many tissue types, including brain tissue. Examining burden scores from singleton exonic SNPs predicted to be deleterious indicated that cases had significantly more mutations than controls (odds ratio, 1.009; 95% CI, 1.003-1.014; P = .003), including those occurring in genes expressed in the brain (odds ratio, 1.011; 95% CI, 1.003-1.018; P = .004) and within nuclear-encoded genes with mitochondrial gene products (odds ratio, 1.075; 95% CI, 1.018-1.135; P = .009).
Conclusions and Relevance
Results support a complex etiology for MDD and highlight the value of analyzing components of heritability to clarify genetic architecture.
Peterson RE, Cai N, Bigdeli TB, Li Y, Reimers M, Nikulova A, Webb BT, Bacanu S, Riley BP, Flint J, Kendler KS. The Genetic Architecture of Major Depressive Disorder in Han Chinese Women. JAMA Psychiatry. 2017;74(2):162-168. doi:10.1001/jamapsychiatry.2016.3578