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Chunk #18 — Results — Gene-based tests

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Genome-wide association study of major depressive disorder: new results, meta-analysis, and lessons learned.
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Of the 183 candidate genes investigated in other GWAS for MDD, we could test for association with 180 (Supplementary File 4). None were associated with P<0.00028 (0.05/180). The six most associated were IL10, OPRM1, HTT, HTR1B, GRIN1 and CACNA1C. Of these, OPRM1 was reported to have P<0.05 in the GAIN–MDD gene-based test and CACNA1C was top ranked in the GenRed13 study; the other studies all used a gene test based on best single associated SNP corrected for gene length. In this study, CACNA1C ranked 808 out of 18 454 (4th percentile). Our top associated SNP in CACNA1C is rs98545 (P=0.0019, OR=0.83, MAF=0.15) which is 387 kb from, and in near linkage equilibrium (r2=0.06) with, rs1006737 (P=0.020, OR=1.10, MAF=0.35), the SNP first identified in genome-wide association studies of bipolar disorder;35 an interaction between these SNPs was not significant (P=0.21). The 3rd ranked of the candidate genes (Huntingtin, HTT) was included in the candidate list because mood disorders are characteristic of presymptomatic carriers of the Huntington's disease trinucleotide repeat polymorphisms.31 HTT ranked in the top 0.7% of all genes; the SNP showing