title: The Genetic Architecture of Major Depressive Disorder in Han Chinese Women.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  Results support a complex etiology for MDD and highlight the value of analyzing components of heritability to clarify genetic architecture.
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Roseann E
authors.initials: RE
authors.lastname: Peterson
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, United Kingdom3European Bioinformatics Institute, Hinxton, United Kingdom.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Tim B
authors.initials: TB
authors.lastname: Bigdeli
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, England.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Neuroscience Program, Michigan State University, East Lansing.
authors.forename: Mark
authors.initials: M
authors.lastname: Reimers
authors.affiliation: A.A. Kharkevich Institute for Information Transmission Problems RAS, Moscow, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Nikulova
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Webb
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Silviu-Alin
authors.initials: SA
authors.lastname: Bacanu
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Brien P
authors.initials: BP
authors.lastname: Riley
authors.affiliation: Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California-Los Angeles.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.affiliation: Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D002874:Chromosome Mapping; D003850:Deoxyribonuclease I / Q000235:genetics; D003865:Major Depressive Disorder / Q000208:ethnology* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005828:Genetics, Population; D006801:Humans; D008875:Middle Aged; D016366:Open Reading Frames / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012306:Risk; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D003850:Deoxyribonuclease I