A fine-mapping study of 7 top scoring genes from a GWAS for major depressive disorder.
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.
Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. e.verbeek@vumc.nl
Eva C
EC
Verbeek
Ingrid M C
IM
Bakker
Marianna R
MR
Bevova
Zoltán
Z
Bochdanovits
Patrizia
P
Rizzu
David
D
Sondervan
Gonneke
G
Willemsen
Eco J
EJ
de Geus
Johannes H
JH
Smit
Brenda W
BW
Penninx
Dorret I
DI
Boomsma
Witte J G
WJ
Hoogendijk
Peter
P
Heutink
D002874:Chromosome Mapping; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics*; D003865:Major Depressive Disorder / Q000235:genetics*; D004843:Epistasis, Genetic / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium; D009426:Netherlands; D009479:Neuropeptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
D003598:Cytoskeletal Proteins; D009479:Neuropeptides; C498630:PCLO protein, human