Deep resequencing and association analysis of schizophrenia candidate genes
作者： J J Crowley , C E Hilliard , Y Kim , M B Morgan , L R Lewis
DOI: 10.1038/MP.2012.28
关键词:
摘要: In 2005, we selected 10 genes for which there was reasonable evidence involvement in the etiology of schizophrenia (COMT, DAOA, DISC1, DRD2, DRD3, DTNBP1, HTR2A, NRG1, SLC6A3, SLC6A4, Table S1)1. Although these have not received support from far larger and comprehensive subsequent studies, may contain etiological common variation2, it is possible that they uncommon variation importance. To test this hypothesis, conducted a multistage resequencing study. In Stage 1, used Sanger methods to sequence exons, 5′ 3′ UTRs, splice sites, promoters conserved intronic regions 727 cases with CATIE3 733 controls European (EUR) African (AFR) ancestry. 2, validated single nucleotide variants (SNVs) using Roche 454 sequencing same samples. 3, genotyped prioritized SNVs independent samples (Supplemental Material Figure S1). In identified 782 variants, including 587 novel found dbSNP132 (Tables S2–S4). As expected, number discovered per individual higher those AFR (1.46) than EUR ancestry (0.95) but did differ (EUR cases/controls: 0.920/0.980; 1.492/1.430). The numbers gene were also similar although DISC1 showed non-significant excess 0.138/0.119; 0.243/0.167) mostly due subjects (cases/controls: 0.173/0.099). Three unrelated cases, zero controls, each nonsense mutation: two (truncating only “Es” variants) one SLC6A4 ratio nonsynonymous synonomous (1.25 vs 1.16). In 254 technical replication since met at least following criteria: 1) nonsense, missense or site variant, 2) variant ≥1 case, 3) an odds >2 cohort, 4) dbSNP case. Validation by revealed 225 true 29 false positives (accuracy rate 89%, S2). In 92 (Table S5) 2 genotyping sample 2,191 2,659 AFR). We included: all seen >1 three observed case each. After samples, monomorphic (22 1), six had low quality genotypes, 57 tested association (logistic regression, separately subjects). 1 lists smallest p-value (complete results S6). No contained SNV reaching criteria genome-wide significance (p < 5 × 10−8). then aggregate effects within 35 non-intronic MAF <0.01 1). significant correction multiple testing. For example, 20 (Figure S3), 32 minor alleles 40 controls. Table 1 Summary 3 results. Thus, ten candidate yield exonic variation. This result consistent do not, date, provide despite size 21,856 individuals. 80% power detect genotypic relative risk 3.2 cohort 5.1 0.01 level P = 5×10−8. relaxed threshold 0.001, would been >99% 2.9 4.6 cohort. The hinted might thus main focus replication. However, no our hypothesis contains relevance as single-SNV approach even nominal significance. present 0 additional particular mutations. DISC1 has dozens genetic studies4. recent meta-analysis its role susceptibility5. knowledge, four groups sequenced schizophrenia6–9, discovery smaller reported here (34, 90, 198 288 cases). Of none Only study component, initial finding replicate9. Therefore, employing times sample, individually associated schizophrenia. The suggest classical harbor coding region
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