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P3–010: Alzheimer's disease: Finding the missing heritability
Author(s) -
Ridge Perry,
Mukherjee Shubhabrata,
Crane Paul,
Kauwe John
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1079
Subject(s) - single nucleotide polymorphism , genome wide association study , snp , biology , genetics , heritability , genetic association , missing heritability problem , explained variation , genetic architecture , quantitative trait locus , gene , genotype , statistics , mathematics
Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, for non-Hispanic Caucasian participants, SNP genotypes (Illumina Human610-Quad BeadChip) were imputed using MACH, and CNV calls were generated using PennCNVas previously described (Swaminathan et al. 2011). All participants were assessed for depressive symptoms using the Geriatric Depression Scale (GDS-15). The total score excluding the memory complaint item was used as the phenotype. Age, sex, education, and CDR Sum-of-Boxes score were used as covariates.For a case-control analysis, all participants were divided into those with (GDS 2; cases) or without (GDS1⁄40; controls) depressive symptoms (Arnold et al. 2012). GWAS, total CNV burden, gene-based case/control CNV, quantitative trait loci (QTL) CNV association analyses were performed. The Health and Retirement Study (HRS) and Indiana Memory and Aging Study (IMAS) were used for meta-analysis to replicate GWAS findings. Results: rs62020725 (IQGAP1) (P 1⁄42.9x10 -8) were identified from GWAS and replicated in the meta-analysis (P 1⁄41.7x10 -5) (Table 1, Figure 1). We identified 5,040 CNVs and found an overall enrichment of deletion CNVs in cases compared with controls (P 1⁄40.03; Table 2). Gene-based case/control analysis identified CNVs overlapping eight candidate genes exclusively in 3 of 134 cases, but not in any of the 241 controls (Table 3). Gene-based QTL analysis identified three additional candidate genes and showed more statistical detection power (Table 3).Conclusions:GWAS indicated that rs62020725 (IQGAP1) is significantly associated with depressive symptoms in older adults. Genome wide CNV analysis identified multiple candidate genes associated with depressive symptoms. IQGAP1 acts as a scaffold for several signaling pathways, which regulate spine density and show marked abnormalities in psychiatric illnesses (Gao et al. 2011). Additional CNV studies with larger sample sizes are needed for replication.