Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.
Anubha MahajanDaniel TaliunMatthias ThurnerNeil R RobertsonJason M TorresN William RaynerAnthony J PayneValgerdur SteinthorsdottirRobert A ScottNiels GrarupJames P CookEllen M SchmidtMatthias WuttkeChloé SarnowskiReedik MägiJana NanoChristian GiegerStella TrompetCécile LecoeurMichael H PreussBram Peter PrinsXiuqing GuoLawrence F BielakJennifer E BelowDonald W BowdenJohn Campbell ChambersYoung Jin KimMaggie C Y NgLauren E PettyXueling SimWeihua ZhangAmanda J BennettJette Bork-JensenChad M BrummettMickaël CanouilKai-Uwe Ec KardtKrista FischerSharon L R KardiaFlorian KronenbergKristi LällChing-Ti LiuAdam E LockeJian'an LuanIoanna NtallaVibe NylanderSebastian SchönherrClaudia SchurmannLoïc YengoErwin P BottingerIvan BrandslundCramer ChristensenGeorge DedoussisJose C FlorezIan FordOscar H FrancoTimothy M FraylingVilmantas GiedraitisSophie HackingerAndrew T HattersleyChristian HerderM Arfan IkramMartin IngelssonMarit E JørgensenTorben JørgensenJennifer KriebelJohanna KuusistoSymen LigthartCecilia M LindgrenAllan LinnebergValeriya LyssenkoVasiliki MamakouThomas MeitingerKaren L MohlkeAndrew D MorrisGirish NadkarniJames S PankowAnnette PetersNaveed SattarAlena StančákováKonstantin StrauchKent D TaylorBarbara ThorandGudmar ThorleifssonUnnur ThorsteinsdottirJaakko TuomilehtoDaniel R WitteJosée DupuisPatricia A PeyserEleftheria ZegginiRuth J F LoosPhilippe FroguelErik IngelssonLars LindLeif GroopMarkku LaaksoFrancis S CollinsJ Wouter JukemaColin N A PalmerHarald GrallertAndres MetspaluAbbas DehghanAnna KöttgenGoncalo R AbecasisJames B MeigsJerome I RotterJonathan MarchiniOluf PedersenTorben HansenClaudia LangenbergNicholas J WarehamKari StefanssonAnna L GloynAndrew P MorrisMichael BoehnkeMark I McCarthyPublished in: Nature genetics (2018)
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
Keyphrases
- high density
- genome wide
- copy number
- type diabetes
- dna methylation
- air pollution
- high throughput
- small molecule
- high resolution
- electronic health record
- cardiovascular disease
- metabolic syndrome
- big data
- risk factors
- glycemic control
- health information
- risk assessment
- deep learning
- artificial intelligence
- mass spectrometry