Incorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problems

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dc.authoridKaprio, Jaakko/0000-0002-3716-2455
dc.authoridWolen, Aaron/0000-0003-2542-2202
dc.authoridSalvatore, Jessica/0000-0001-5504-5087
dc.authoridSavage, Jeanne/0000-0002-2034-8341
dc.authoridVuoksimaa, Eero/0000-0002-6534-3667
dc.authoridLatvala, Antti/0000-0001-5695-117X
dc.contributor.authorSalvatore, Jessica E.
dc.contributor.authorSavage, Jeanne E.
dc.contributor.authorBarr, Peter
dc.contributor.authorWolen, Aaron R.
dc.contributor.authorAliev, Fazil
dc.contributor.authorVuoksimaa, Eero
dc.contributor.authorLatvala, Antti
dc.date.accessioned2024-09-29T16:04:32Z
dc.date.available2024-09-29T16:04:32Z
dc.date.issued2018
dc.departmentKarabük Üniversitesien_US
dc.description.abstractBackgroundCharacterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene-by-environment (GxE) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit GxE effects. MethodsWe examined these questions in the young adult FinnTwin12 sample (n=1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p-value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the GxE analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant GxE effects in an interaction between romantic relationship status and intoxication frequency. ResultsContrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per-SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In GxE models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. ConclusionsThese findings highlight the potential utility of integrating functional genomic annotation information to increase the signal-to-noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification.en_US
dc.description.sponsorshipNational Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health [R01AA015416, K02AA018755, F31AA024378, K01AA024152]; National Institute of Mental Health [T32MH20030]; Academy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; Scientific and Technological Research Council of Turkey (TUBITAK) [114C117]en_US
dc.description.sponsorshipFunding for this work came from the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award numbers R01AA015416, K02AA018755, F31AA024378, and K01AA024152; the National Institute of Mental Health (T32MH20030); the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278, and 264146); and the Scientific and Technological Research Council of Turkey (TUBITAK) under award number 114C117. Genotyping of the FinnTwin12 sample was supported also by the Wellcome Trust Sanger Centre. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Academy of Finland, or the Scientific and Technological Research Council of Turkey.en_US
dc.identifier.doi10.1111/acer.13551
dc.identifier.endpage423en_US
dc.identifier.issn0145-6008
dc.identifier.issn1530-0277
dc.identifier.issue2en_US
dc.identifier.pmid29121402en_US
dc.identifier.scopus2-s2.0-85038367270en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage413en_US
dc.identifier.urihttps://doi.org/10.1111/acer.13551
dc.identifier.urihttps://hdl.handle.net/20.500.14619/6195
dc.identifier.volume42en_US
dc.identifier.wosWOS:000423381600022en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.ispartofAlcoholism-Clinical and Experimental Researchen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectAlcoholen_US
dc.subjectFunctional Genomicsen_US
dc.subjectGene-Environment Interplayen_US
dc.subjectPolygenic Scoresen_US
dc.titleIncorporating Functional Genomic Information to Enhance Polygenic Signal and Identify Variants Involved in Gene-by-Environment Interaction for Young Adult Alcohol Problemsen_US
dc.typeArticleen_US

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