The Genetic Architecture of Major Depressive Disorder in Han Chinese Women

Abstract

IMPORTANCE 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. OBJECTIVES 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. RESULTS 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.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depressive disorder

“…In the CONVERGE sample, was reported as 20-29%. 128 Its r g with the seven European MDD cohorts was 0.33 (SE 0.03). 129 For comparison, r g for CONVERGE with European results for schizophrenia was 0.34 (SE 0.05) and 0.45 (SE 0.07) for bipolar disorder.…”

Genetics of Depression: Progress at Last

“…The for depressive symptoms from the total sample was 0.04 (s.e. 0.004), which is considerably lower than the estimates from clinically ascertained MDD samples (~0.2 in both the PGC and CONVERGE studies) [9, 27]. This may result from mixing heterogeneous measures of depression which are influenced by different combinations of genetic variants and the weak information on depression symptoms from just two questions.…”

Rapporteur summaries of plenary, symposia, and oral sessions from the XXIIIrd World Congress of Psychiatric Genetics Meeting in Toronto, Canada, 16–20 October 2015

“…Dr. Kendler reported that they successfully detected and replicated two common variants contributing to MDD risk on chromosome 10q: upstream of SIRT1 and in an intron of LHPP (Converge Consortium, 2015). He also commented on the genetic architecture of MDD, reporting that (1) genome-wide SNP-based heritability was estimated as 21-28%, (2) the heritability in MDD explained by each chromosome was proportional to its length (r=0.680) thus supporting a highly polygenic etiology, (3) the variance explained was distributed across the allelic frequency spectrum, (4) partitioning by genic annotation indicated a greater contribution of SNPs in coding regions and within the 3′-UTR regions, and (5) that DNase hypersensitive sites in many cell types including brain-related cells were enriched for associations with MDD (Peterson et al, submitted to Mol Psychiatry ).…”