title: Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer's disease GWAS findings.
abstract: Late-onset Alzheimer's disease (LOAD) is a multifactorial disorder with over twenty loci associated with disease risk. Given the number of genome-wide significant variants that fall outside of coding regions, it is possible that some of these variants alter some function of gene expression rather than tagging coding variants that alter protein structure and/or function. RegulomeDB is a database that annotates regulatory functions of genetic variants. In this study, we utilized RegulomeDB to investigate potential regulatory functions of lead single nucleotide polymorphisms (SNPs) identified in five genome-wide association studies (GWAS) of risk and age-at onset (AAO) of LOAD, as well as SNPs in LD (r2≥0.80) with the lead GWAS SNPs. Of a total 614 SNPs examined, 394 returned RegulomeDB scores of 1-6. Of those 394 variants, 34 showed strong evidence of regulatory function (RegulomeDB score <3), and only 3 of them were genome-wide significant SNPs (ZCWPW1/rs1476679, CLU/rs1532278 and ABCA7/rs3764650). This study further supports the assumption that some of the non-coding GWAS SNPs are true associations rather than tagged associations and demonstrates the application of RegulomeDB to GWAS data.
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Rosenthal
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: M Michael
authors.initials: MM
authors.lastname: Barmada
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Xingbin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: F Yesim
authors.initials: FY
authors.lastname: Demirci
authors.affiliation: Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America; Alzheimer's Disease Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: M Ilyas
authors.initials: MI
authors.lastname: Kamboh
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000544:Alzheimer Disease / Q000235:genetics*; D051152:Clusterin / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: C411895:ABCA7 protein, human; D018528:ATP-Binding Cassette Transporters; C495242:CLU protein, human; D051152:Clusterin
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