Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.
Josine L MinGibran HemaniEilis J HannonKoen F DekkersJuan E Castillo-FernandezRené LuijkElena Carnero-MontoroDaniel John LawsonKimberley BurrowsMatthew SudermanAndrew D BretherickTom G RichardsonJohanna KlughammerValentina IotchkovaGemma C SharpAhmad Al KhleifatAleksey ShatunovAlfredo IacoangeliWendy L McArdleKaren M HoAshish KumarCilla SöderhällCarolina Soriano-TárragaEva Giralt-SteinhauerNabila KazmiDan MasonAllan F McRaeDavid L CorcoranKaren SugdenSilva KaselaAlexia CardonaFelix R DayGiovanni CugliariClara VibertiSimonetta GuarreraMichael LerroRicha GuptaSailalitha BollepalliPooja MandaviyaYanni ZengToni-Kim ClarkeRosie M WalkerVanessa SchmollDarina CzamaraCarlos Ruiz-ArenasFaisal I RezwanRiccardo E MarioniTian LinYvonne AwaloffMarine GermainDylan AïssiRamona ZwambornKristel van EijkAnnelot DekkerJenny Van DongenJouke- Jan HottengaGonneke WillemsenCheng-Jian XuGuillermo BarturenFrancesc Català-MollMartin KerickCarol A WangPhillip E MeltonHannah R ElliottJean ShinManon BernardIdil YetMelissa SmartTyler J Gorrie-Stonenull nullChris ShawAmmar Al ChalabiSusan M RingGöran PershagenErik MelénJordi Jiménez-CondeJaume RoquerDeborah A LawlorJohn WrightNicholas G MartinGrant W MontgomeryTerrie E MoffittRichie PoultonTõnu EskoLili A MilaniAndres MetspaluJohn R B PerryKen K OngNicholas J WarehamGiuseppe MatulloCarlotta SacerdoteSalvatore PanicoAvshalom CaspiLouise ArseneaultFrance GagnonMiina OllikainenJaakko A KaprioJanine F FelixFernando RivadeneiraHenning TiemeierMarinus van IJzendoornAndre G UitterlindenVincent W V JaddoeChris HaleyAndrew M McIntoshKathryn L EvansAlison D MurrayKatri RäikkönenJari M T LahtiEllen A NohrThorkild I A SørensenTorben HansenCamilla S MorgenElisabeth B BinderSusanne LucaeJuan Ramon GonzálezMariona BustamanteJordi SunyerJohn W HollowayWilfried KarmausHongmei ZhangIan J DearyNaomi R WrayJohn M StarrMarian BeekmanDiana van HeemstPieternella Eline SlagboomPierre-Emmanuel MorangeDavid-Alexandre TrégouëtJan Herman VeldinkGareth E DaviesEco J C de GeusDorret I BoomsmaJudith E VonkBert BrunekreefGerard H KoppelmannMarta Eugenia Alarcón-RiquelmeRae-Chi HuangCraig E PennellJoyce van MeursMohammad Arfan IkramAlun D HughesTherese TillinNish ChaturvediZdenka PausovaTomáš PausTimothy D SpectorMeena KumariLeonard C SchalkwykPeter M VisscherGeorge Davey SmithChristoph BockTom R GauntJordana T BellBastiaan T HeijmansJonathan S MillCaroline L ReltonPublished in: Nature genetics (2021)
Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.