A fine-mapping study of 7 top scoring genes from a GWAS for major depressive disorder

PLoS One. 2012;7(5):e37384. doi: 10.1371/journal.pone.0037384. Epub 2012 May 23.

Abstract

Major depressive disorder (MDD) is a psychiatric disorder that is characterized--amongst others--by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r(2)>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E-7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E-6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E-7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Mapping
  • Cohort Studies
  • Cytoskeletal Proteins / genetics*
  • Depressive Disorder, Major / genetics*
  • Epistasis, Genetic / genetics
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Linkage Disequilibrium
  • Netherlands
  • Neuropeptides / genetics*
  • Polymorphism, Single Nucleotide / genetics*

Substances

  • Cytoskeletal Proteins
  • Neuropeptides
  • PCLO protein, human