04013nas a2201093 4500008004100000022001400041245012400055210006900179260000900248300000900257490000600266520085300272653003801125653001601163653001901179653003201198653001101230653002301241653001601264100003001280700002401310700001801334700001801352700002801370700001801398700002701416700002001443700001801463700001801481700002801499700002501527700002201552700002101574700002001595700002101615700002001636700002001656700002001676700002101696700002301717700002001740700002101760700002701781700002601808700002401834700001901858700002601877700001901903700001901922700002101941700002401962700002001986700002502006700001602031700001902047700002202066700002302088700001902111700002202130700002402152700002302176700001902199700002202218700002602240700002002266700001502286700002102301700002102322700002202343700001902365700002202384700001602406700002002422700002102442700002002463700002302483700002502506700002002531700002202551700001902573700001502592700002302607700002402630700002802654700002202682700002702704700002502731700002002756700002302776700002002799700002302819710004102842856003602883 2015 eng d a2041-172300aGenome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.0 aGenome of The Netherlands populationspecific imputations identif c2015 a60650 v63 a
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
10aATP-Binding Cassette Transporters10aCholesterol10aGene Frequency10aGenetic Association Studies10aHumans10aMutation, Missense10aNetherlands1 avan Leeuwen, Elisabeth, M1 aKarssen, Lennart, C1 aDeelen, Joris1 aIsaacs, Aaron1 aMedina-Gómez, Carolina1 aMbarek, Hamdi1 aKanterakis, Alexandros1 aTrompet, Stella1 aPostmus, Iris1 aVerweij, Niek1 avan Enckevort, David, J1 aHuffman, Jennifer, E1 aWhite, Charles, C1 aFeitosa, Mary, F1 aBartz, Traci, M1 aManichaikul, Ani1 aJoshi, Peter, K1 aPeloso, Gina, M1 aDeelen, Patrick1 avan Dijk, Freerk1 aWillemsen, Gonneke1 ade Geus, Eco, J1 aMilaneschi, Yuri1 aPenninx, Brenda, W J H1 aFrancioli, Laurent, C1 aMenelaou, Androniki1 aPulit, Sara, L1 aRivadeneira, Fernando1 aHofman, Albert1 aOostra, Ben, A1 aFranco, Oscar, H1 aLeach, Irene, Mateo1 aBeekman, Marian1 ade Craen, Anton, J M1 aUh, Hae-Won1 aTrochet, Holly1 aHocking, Lynne, J1 aPorteous, David, J1 aSattar, Naveed1 aPackard, Chris, J1 aBuckley, Brendan, M1 aBrody, Jennifer, A1 aBis, Joshua, C1 aRotter, Jerome, I1 aMychaleckyj, Josyf, C1 aCampbell, Harry1 aDuan, Qing1 aLange, Leslie, A1 aWilson, James, F1 aHayward, Caroline1 aPolasek, Ozren1 aVitart, Veronique1 aRudan, Igor1 aWright, Alan, F1 aRich, Stephen, S1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aKearney, Patricia, M1 aStott, David, J1 aCupples, Adrienne1 aJukema, Wouter1 aHarst, Pim1 aSijbrands, Eric, J1 aHottenga, Jouke-Jan1 aUitterlinden, André, G1 aSwertz, Morris, A1 avan Ommen, Gert-Jan, B1 ade Bakker, Paul, I W1 aSlagboom, Eline1 aBoomsma, Dorret, I1 aWijmenga, Cisca1 aDuijn, Cornelia, M1 aGenome of the Netherlands Consortium uhttps://chs-nhlbi.org/node/668204625nas a2201021 4500008004100000022001400041245006600055210006500121260001300186300001200199490000700211520174100218100001601959700002501975700002502000700002802025700001502053700002402068700002202092700001602114700002402130700001802154700002502172700002302197700002602220700001902246700001602265700001802281700001902299700002102318700001802339700002302357700002202380700002302402700002002425700001602445700002102461700002002482700002002502700002402522700001902546700001802565700001702583700002602600700002002626700002002646700002302666700001202689700002402701700002502725700003002750700002402780700002402804700002302828700002802851700002602879700003002905700002502935700002502960700001902985700002403004700001903028700002003047700002403067700002103091700002603112700002103138700001903159700002303178700001903201700002003220700002103240700001903261700002303280700002403303700002303327700002403350700001603374700002203390700002803412700002303440700002103463700002203484700001703506700002103523700002303544856003603567 2016 eng d a1476-543800aGenetic variants in RBFOX3 are associated with sleep latency.0 aGenetic variants in RBFOX3 are associated with sleep latency c2016 Oct a1488-950 v243 aTime to fall asleep (sleep latency) is a major determinant of sleep quality. Chronic, long sleep latency is a major characteristic of sleep-onset insomnia and/or delayed sleep phase syndrome. In this study we aimed to discover common polymorphisms that contribute to the genetics of sleep latency. We performed a meta-analysis of genome-wide association studies (GWAS) including 2 572 737 single nucleotide polymorphisms (SNPs) established in seven European cohorts including 4242 individuals. We found a cluster of three highly correlated variants (rs9900428, rs9907432 and rs7211029) in the RNA-binding protein fox-1 homolog 3 gene (RBFOX3) associated with sleep latency (P-values=5.77 × 10(-08), 6.59 × 10(-)(08) and 9.17 × 10(-)(08)). These SNPs were replicated in up to 12 independent populations including 30 377 individuals (P-values=1.5 × 10(-)(02), 7.0 × 10(-)(03) and 2.5 × 10(-)(03); combined meta-analysis P-values=5.5 × 10(-07), 5.4 × 10(-07) and 1.0 × 10(-07)). A functional prediction of RBFOX3 based on co-expression with other genes shows that this gene is predominantly expressed in brain (P-value=1.4 × 10(-316)) and the central nervous system (P-value=7.5 × 10(-)(321)). The predicted function of RBFOX3 based on co-expression analysis with other genes shows that this gene is significantly involved in the release cycle of neurotransmitters including gamma-aminobutyric acid and various monoamines (P-values<2.9 × 10(-11)) that are crucial in triggering the onset of sleep. To conclude, in this first large-scale GWAS of sleep latency we report a novel association of variants in RBFOX3 gene. Further, a functional prediction of RBFOX3 supports the involvement of RBFOX3 with sleep latency.
1 aAmin, Najaf1 aAllebrandt, Karla, V1 avan der Spek, Ashley1 aMüller-Myhsok, Bertram1 aHek, Karin1 aTeder-Laving, Maris1 aHayward, Caroline1 aEsko, Tõnu1 avan Mill, Josine, G1 aMbarek, Hamdi1 aWatson, Nathaniel, F1 aMelville, Scott, A1 aDel Greco, Fabiola, M1 aByrne, Enda, M1 aOole, Edwin1 aKolcic, Ivana1 aChen, Ting-Hsu1 aEvans, Daniel, S1 aCoresh, Josef1 aVogelzangs, Nicole1 aKarjalainen, Juha1 aWillemsen, Gonneke1 aGharib, Sina, A1 aZgaga, Lina1 aMihailov, Evelin1 aStone, Katie, L1 aCampbell, Harry1 aBrouwer, Rutger, Ww1 aDemirkan, Ayse1 aIsaacs, Aaron1 aDogas, Zoran1 aMarciante, Kristin, D1 aCampbell, Susan1 aBorovecki, Fran1 aLuik, Annemarie, I1 aLi, Man1 aHottenga, Jouke Jan1 aHuffman, Jennifer, E1 avan den Hout, Mirjam, Cgn1 aCummings, Steven, R1 aAulchenko, Yurii, S1 aGehrman, Philip, R1 aUitterlinden, André, G1 aWichmann, Heinz-Erich1 aMüller-Nurasyid, Martina1 aFehrmann, Rudolf, Sn1 aMontgomery, Grant, W1 aHofman, Albert1 aKao, Wen Hong Linda1 aOostra, Ben, A1 aWright, Alan, F1 aVink, Jacqueline, M1 aWilson, James, F1 aPramstaller, Peter, P1 aHicks, Andrew, A1 aPolasek, Ozren1 aPunjabi, Naresh, M1 aRedline, Susan1 aPsaty, Bruce, M1 aHeath, Andrew, C1 aMerrow, Martha1 aTranah, Gregory, J1 aGottlieb, Daniel, J1 aBoomsma, Dorret, I1 aMartin, Nicholas, G1 aRudan, Igor1 aTiemeier, Henning1 avan IJcken, Wilfred, Fj1 aPenninx, Brenda, W1 aMetspalu, Andres1 aMeitinger, Thomas1 aFranke, Lude1 aRoenneberg, Till1 aDuijn, Cornelia, M uhttps://chs-nhlbi.org/node/716805543nas a2201657 4500008004100000022001400041245013300055210007000188260001600258300001600274490000800290520094500298100002101243700001601264700001901280700001201299700001901311700001301330700002101343700001601364700001601380700001701396700002601413700001801439700002301457700002601480700002101506700002101527700001901548700002001567700002101587700002101608700001901629700001701648700002401665700001901689700002001708700002101728700002001749700002101769700001701790700001801807700002801825700002101853700002101874700001801895700002101913700002201934700002101956700002401977700002402001700002002025700001802045700002302063700001602086700001702102700001902119700002202138700002302160700001802183700002602201700001902227700002202246700002002268700002802288700002402316700002602340700001802366700002202384700002202406700001902428700001602447700001302463700001802476700001902494700002302513700001902536700002302555700002102578700001702599700001502616700002302631700001602654700002202670700002102692700002202713700002202735700001902757700002402776700002002800700002202820700002802842700002102870700001902891700001902910700001902929700002702948700001902975700001902994700002203013700002103035700001603056700002403072700002203096700001703118700002403135700002103159700002103180700002003201700002003221700001703241700002003258700001703278700001803295700002203313700002203335700002003357700002003377700001703397700002003414700002103434700001503455700002303470700002503493700002403518700002503542700002303567700001803590700002503608700002103633700002503654700001303679700002103692700002603713700002303739700002603762700002603788700001703814700001803831856003603849 2016 eng d a1091-649000aKLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference.0 aKLB is associated with alcohol drinking and its gene product βKl c2016 Dec 13 a14372-143770 v1133 aExcessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
1 aSchumann, Gunter1 aLiu, Chunyu1 aO'Reilly, Paul1 aGao, He1 aSong, Parkyong1 aXu, Bing1 aRuggeri, Barbara1 aAmin, Najaf1 aJia, Tianye1 aPreis, Sarah1 aLepe, Marcelo, Segura1 aAkira, Shizuo1 aBarbieri, Caterina1 aBaumeister, Sebastian1 aCauchi, Stephane1 aClarke, Toni-Kim1 aEnroth, Stefan1 aFischer, Krista1 aHällfors, Jenni1 aHarris, Sarah, E1 aHieber, Saskia1 aHofer, Edith1 aHottenga, Jouke-Jan1 aJohansson, Asa1 aJoshi, Peter, K1 aKaartinen, Niina1 aLaitinen, Jaana1 aLemaitre, Rozenn1 aLoukola, Anu1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMangino, Massimo1 aManichaikul, Ani1 aMbarek, Hamdi1 aMilaneschi, Yuri1 aMoayyeri, Alireza1 aMukamal, Kenneth1 aNelson, Christopher1 aNettleton, Jennifer1 aPartinen, Eemil1 aRawal, Rajesh1 aRobino, Antonietta1 aRose, Lynda1 aSala, Cinzia1 aSatoh, Takashi1 aSchmidt, Reinhold1 aSchraut, Katharina1 aScott, Robert1 aSmith, Albert, Vernon1 aStarr, John, M1 aTeumer, Alexander1 aTrompet, Stella1 aUitterlinden, André, G1 aVenturini, Cristina1 aVergnaud, Anne-Claire1 aVerweij, Niek1 aVitart, Veronique1 aVuckovic, Dragana1 aWedenoja, Juho1 aYengo, Loic1 aYu, Bing1 aZhang, Weihua1 aZhao, Jing Hua1 aBoomsma, Dorret, I1 aChambers, John1 aChasman, Daniel, I1 aDaniela, Toniolo1 ade Geus, Eco1 aDeary, Ian1 aEriksson, Johan, G1 aEsko, Tõnu1 aEulenburg, Volker1 aFranco, Oscar, H1 aFroguel, Philippe1 aGieger, Christian1 aGrabe, Hans, J1 aGudnason, Vilmundur1 aGyllensten, Ulf1 aHarris, Tamara, B1 aHartikainen, Anna-Liisa1 aHeath, Andrew, C1 aHocking, Lynne1 aHofman, Albert1 aHuth, Cornelia1 aJarvelin, Marjo-Riitta1 aJukema, Wouter1 aKaprio, Jaakko1 aKooner, Jaspal, S1 aKutalik, Zoltán1 aLahti, Jari1 aLangenberg, Claudia1 aLehtimäki, Terho1 aLiu, Yongmei1 aMadden, Pamela, A F1 aMartin, Nicholas1 aMorrison, Alanna1 aPenninx, Brenda1 aPirastu, Nicola1 aPsaty, Bruce1 aRaitakari, Olli1 aRidker, Paul1 aRose, Richard1 aRotter, Jerome, I1 aSamani, Nilesh, J1 aSchmidt, Helena1 aSpector, Tim, D1 aStott, David1 aStrachan, David1 aTzoulaki, Ioanna1 aHarst, Pim1 aDuijn, Cornelia, M1 aMarques-Vidal, Pedro1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWhitfield, John, B1 aWilson, James1 aWolffenbuttel, Bruce1 aBakalkin, Georgy1 aEvangelou, Evangelos1 aLiu, Yun1 aRice, Kenneth, M1 aDesrivières, Sylvane1 aKliewer, Steven, A1 aMangelsdorf, David, J1 aMüller, Christian, P1 aLevy, Daniel1 aElliott, Paul uhttps://chs-nhlbi.org/node/725604981nas a2201333 4500008004100000022001400041245015700055210006900212260001300281300001000294490000700304520112400311100003001435700001601465700001901481700002501500700002101525700002101546700002101567700002301588700002001611700001501631700002101646700002401667700001701691700001901708700001801727700001801745700002001763700002001783700001801803700002501821700002801846700002201874700001801896700002701914700002801941700001901969700002101988700001902009700002102028700001902049700002602068700002302094700002802117700002602145700002102171700002202192700002502214700002302239700002102262700002202283700001902305700001802324700002002342700002102362700001602383700001802399700001702417700002202434700002002456700002102476700002202497700002002519700002202539700002002561700002002581700002102601700002702622700002302649700002302672700001402695700002302709700002802732700002302760700002202783700001702805700002402822700002302846700002502869700002602894700002302920700002002943700002902963700002002992700002303012700002003035700002203055700001803077700001503095700001903110700002903129700002303158700002203181700001903203700002003222700002603242700002203268700001903290700002203309700002103331700002103352700002403373700002103397700002003418700002303438700002103461700002203482700002503504700002303529710002703552710003203579856003603611 2016 eng d a1468-624400aMeta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels.0 aMetaanalysis of 49 549 individuals imputed with the 1000 Genomes c2016 Jul a441-90 v533 aBACKGROUND: So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.
METHODS: We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.
RESULTS: Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.
CONCLUSIONS: This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.
1 avan Leeuwen, Elisabeth, M1 aSabo, Aniko1 aBis, Joshua, C1 aHuffman, Jennifer, E1 aManichaikul, Ani1 aSmith, Albert, V1 aFeitosa, Mary, F1 aDemissie, Serkalem1 aJoshi, Peter, K1 aDuan, Qing1 aMarten, Jonathan1 avan Klinken, Jan, B1 aSurakka, Ida1 aNolte, Ilja, M1 aZhang, Weihua1 aMbarek, Hamdi1 aLi-Gao, Ruifang1 aTrompet, Stella1 aVerweij, Niek1 aEvangelou, Evangelos1 aLyytikäinen, Leo-Pekka1 aTayo, Bamidele, O1 aDeelen, Joris1 avan der Most, Peter, J1 avan der Laan, Sander, W1 aArking, Dan, E1 aMorrison, Alanna1 aDehghan, Abbas1 aFranco, Oscar, H1 aHofman, Albert1 aRivadeneira, Fernando1 aSijbrands, Eric, J1 aUitterlinden, André, G1 aMychaleckyj, Josyf, C1 aCampbell, Archie1 aHocking, Lynne, J1 aPadmanabhan, Sandosh1 aBrody, Jennifer, A1 aRice, Kenneth, M1 aWhite, Charles, C1 aHarris, Tamara1 aIsaacs, Aaron1 aCampbell, Harry1 aLange, Leslie, A1 aRudan, Igor1 aKolcic, Ivana1 aNavarro, Pau1 aZemunik, Tatijana1 aSalomaa, Veikko1 aKooner, Angad, S1 aKooner, Jaspal, S1 aLehne, Benjamin1 aScott, William, R1 aTan, Sian-Tsung1 ade Geus, Eco, J1 aMilaneschi, Yuri1 aPenninx, Brenda, W J H1 aWillemsen, Gonneke1 ade Mutsert, Renée1 aFord, Ian1 aGansevoort, Ron, T1 aSegura-Lepe, Marcelo, P1 aRaitakari, Olli, T1 aViikari, Jorma, S1 aNikus, Kjell1 aForrester, Terrence1 aMcKenzie, Colin, A1 ade Craen, Anton, J M1 ade Ruijter, Hester, M1 aPasterkamp, Gerard1 aSnieder, Harold1 aOldehinkel, Albertine, J1 aSlagboom, Eline1 aCooper, Richard, S1 aKähönen, Mika1 aLehtimäki, Terho1 aElliott, Paul1 aHarst, Pim1 aJukema, Wouter1 aMook-Kanamori, Dennis, O1 aBoomsma, Dorret, I1 aChambers, John, C1 aSwertz, Morris1 aRipatti, Samuli1 avan Dijk, Ko, Willems1 aVitart, Veronique1 aPolasek, Ozren1 aHayward, Caroline1 aWilson, James, G1 aWilson, James, F1 aGudnason, Vilmundur1 aRich, Stephen, S1 aPsaty, Bruce, M1 aBorecki, Ingrid, B1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aCupples, Adrienne, L1 aDuijn, Cornelia, M1 aLifeLines Cohort Study1 aCHARGE Lipids Working Group uhttps://chs-nhlbi.org/node/701107136nas a2202245 4500008004100000022001400041245011700055210006900172260001300241300001000254490000700264520074900271100002301020700003301043700002401076700002601100700002301126700001301149700001701162700002001179700002101199700001701220700001901237700003201256700002101288700002301309700002301332700002501355700003101380700002101411700002201432700002201454700002401476700001701500700002201517700002101539700003101560700002001591700002001611700001801631700002501649700003101674700002501705700002101730700001701751700002301768700002001791700002101811700002101832700002401853700002201877700001801899700001901917700002001936700001801956700001801974700002001992700002102012700002002033700002402053700002802077700001902105700002302124700001902147700002202166700002402188700002002212700002102232700002002253700002402273700001902297700001802316700002002334700002202354700001602376700001902392700002102411700002502432700001602457700002102473700002702494700002002521700001802541700002502559700002202584700002102606700002002627700002102647700002602668700002402694700002502718700002402743700001902767700001902786700001802805700001802823700002102841700001902862700002002881700002302901700001802924700001702942700001802959700002202977700002302999700002103022700001203043700001803055700002003073700002503093700001803118700002103136700002003157700002603177700002503203700002303228700002103251700001803272700002203290700001703312700001703329700002003346700001703366700002003383700002003403700002103423700003003444700001903474700002403493700002603517700002303543700001903566700001903585700002203604700002203626700002203648700002203670700002603692700002303718700002203741700002303763700002603786700002103812700002403833700002103857700002303878700002003901700002203921700001803943700002603961700002203987700002004009700002104029700002004050700002204070700001804092700002104110700002304131700002304154700002304177700002404200700002504224700002804249700002404277700002304301700002304324700002804347700002804375700001904403700002204422700002104444700002204465700002004487700002004507700002104527700002004548700002004568700002004588700002104608700002304629700002004652700002104672700001904693700001904712700002304731700001704754700002004771710006304791856003604854 2018 eng d a1546-171800aMultiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.0 aMultiancestry association study identifies new asthma risk loci c2018 Jan a42-530 v503 aWe examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.
1 aDemenais, Florence1 aMargaritte-Jeannin, Patricia1 aBarnes, Kathleen, C1 aCookson, William, O C1 aAltmüller, Janine1 aAng, Wei1 aBarr, Graham1 aBeaty, Terri, H1 aBecker, Allan, B1 aBeilby, John1 aBisgaard, Hans1 aBjornsdottir, Unnur, Steina1 aBleecker, Eugene1 aBønnelykke, Klaus1 aBoomsma, Dorret, I1 aBouzigon, Emmanuelle1 aBrightling, Christopher, E1 aBrossard, Myriam1 aBrusselle, Guy, G1 aBurchard, Esteban1 aBurkart, Kristin, M1 aBush, Andrew1 aChan-Yeung, Moira1 aChung, Kian, Fan1 aAlves, Alexessander, Couto1 aCurtin, John, A1 aCustovic, Adnan1 aDaley, Denise1 ade Jongste, Johan, C1 aDel-Rio-Navarro, Blanca, E1 aDonohue, Kathleen, M1 aDuijts, Liesbeth1 aEng, Celeste1 aEriksson, Johan, G1 aFarrall, Martin1 aFedorova, Yuliya1 aFeenstra, Bjarke1 aFerreira, Manuel, A1 aFreidin, Maxim, B1 aGajdos, Zofia1 aGauderman, Jim1 aGehring, Ulrike1 aGeller, Frank1 aGenuneit, Jon1 aGharib, Sina, A1 aGilliland, Frank1 aGranell, Raquel1 aGraves, Penelope, E1 aGudbjartsson, Daniel, F1 aHaahtela, Tari1 aHeckbert, Susan, R1 aHeederik, Dick1 aHeinrich, Joachim1 aHeliövaara, Markku1 aHenderson, John1 aHimes, Blanca, E1 aHirose, Hiroshi1 aHirschhorn, Joel, N1 aHofman, Albert1 aHolt, Patrick1 aHottenga, Jouke1 aHudson, Thomas, J1 aHui, Jennie1 aImboden, Medea1 aIvanov, Vladimir1 aJaddoe, Vincent, W V1 aJames, Alan1 aJanson, Christer1 aJarvelin, Marjo-Riitta1 aJarvis, Deborah1 aJones, Graham1 aJonsdottir, Ingileif1 aJousilahti, Pekka1 aKabesch, Michael1 aKähönen, Mika1 aKantor, David, B1 aKarunas, Alexandra, S1 aKhusnutdinova, Elza1 aKoppelman, Gerard, H1 aKozyrskyj, Anita, L1 aKreiner, Eskil1 aKubo, Michiaki1 aKumar, Rajesh1 aKumar, Ashish1 aKuokkanen, Mikko1 aLahousse, Lies1 aLaitinen, Tarja1 aLaprise, Catherine1 aLathrop, Mark1 aLau, Susanne1 aLee, Young-Ae1 aLehtimäki, Terho1 aLetort, Sébastien1 aLevin, Albert, M1 aLi, Guo1 aLiang, Liming1 aLoehr, Laura, R1 aLondon, Stephanie, J1 aLoth, Daan, W1 aManichaikul, Ani1 aMarenholz, Ingo1 aMartinez, Fernando, J1 aMatheson, Melanie, C1 aMathias, Rasika, A1 aMatsumoto, Kenji1 aMbarek, Hamdi1 aMcArdle, Wendy, L1 aMelbye, Mads1 aMelén, Erik1 aMeyers, Deborah1 aMichel, Sven1 aMohamdi, Hamida1 aMusk, Arthur, W1 aMyers, Rachel, A1 aNieuwenhuis, Maartje, A E1 aNoguchi, Emiko1 aO'Connor, George, T1 aOgorodova, Ludmila, M1 aPalmer, Cameron, D1 aPalotie, Aarno1 aPark, Julie, E1 aPennell, Craig, E1 aPershagen, Göran1 aPolonikov, Alexey1 aPostma, Dirkje, S1 aProbst-Hensch, Nicole1 aPuzyrev, Valery, P1 aRaby, Benjamin, A1 aRaitakari, Olli, T1 aRamasamy, Adaikalavan1 aRich, Stephen, S1 aRobertson, Colin, F1 aRomieu, Isabelle1 aSalam, Muhammad, T1 aSalomaa, Veikko1 aSchlünssen, Vivi1 aScott, Robert1 aSelivanova, Polina, A1 aSigsgaard, Torben1 aSimpson, Angela1 aSiroux, Valérie1 aSmith, Lewis, J1 aSolodilova, Maria1 aStandl, Marie1 aStefansson, Kari1 aStrachan, David, P1 aStricker, Bruno, H1 aTakahashi, Atsushi1 aThompson, Philip, J1 aThorleifsson, Gudmar1 aThorsteinsdottir, Unnur1 aTiesler, Carla, M T1 aTorgerson, Dara, G1 aTsunoda, Tatsuhiko1 aUitterlinden, André, G1 avan der Valk, Ralf, J P1 aVaysse, Amaury1 aVedantam, Sailaja1 avon Berg, Andrea1 avon Mutius, Erika1 aVonk, Judith, M1 aWaage, Johannes1 aWareham, Nick, J1 aWeiss, Scott, T1 aWhite, Wendy, B1 aWickman, Magnus1 aWiden, Elisabeth1 aWillemsen, Gonneke1 aWilliams, Keoki1 aWouters, Inge, M1 aYang, James, J1 aZhao, Jing Hua1 aMoffatt, Miriam, F1 aOber, Carole1 aNicolae, Dan, L1 aAustralian Asthma Genetics Consortium (AAGC) collaborators uhttps://chs-nhlbi.org/node/755811212nas a2203445 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2021 eng d a1476-468700aGenetic insights into biological mechanisms governing human ovarian ageing.0 aGenetic insights into biological mechanisms governing human ovar c2021 Aug a393-3970 v5963 aReproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
1 aRuth, Katherine, S1 aDay, Felix, R1 aHussain, Jazib1 aMartínez-Marchal, Ana1 aAiken, Catherine, E1 aAzad, Ajuna1 aThompson, Deborah, J1 aKnoblochova, Lucie1 aAbe, Hironori1 aTarry-Adkins, Jane, L1 aGonzalez, Javier, Martin1 aFontanillas, Pierre1 aClaringbould, Annique1 aBakker, Olivier, B1 aSulem, Patrick1 aWalters, Robin, G1 aTerao, Chikashi1 aTuron, Sandra1 aHorikoshi, Momoko1 aLin, Kuang1 aOnland-Moret, Charlotte, N1 aSankar, Aditya1 aHertz, Emil, Peter Thra1 aTimshel, Pascal, N1 aShukla, Vallari1 aBorup, Rehannah1 aOlsen, Kristina, W1 aAguilera, Paula1 aFerrer-Roda, Mònica1 aHuang, Yan1 aStankovic, Stasa1 aTimmers, Paul, R H J1 aAhearn, Thomas, U1 aAlizadeh, Behrooz, Z1 aNaderi, Elnaz1 aAndrulis, Irene, L1 aArnold, Alice, M1 aAronson, Kristan, J1 aAugustinsson, Annelie1 aBandinelli, Stefania1 aBarbieri, Caterina, M1 aBeaumont, Robin, N1 aBecher, Heiko1 aBeckmann, Matthias, W1 aBenonisdottir, Stefania1 aBergmann, Sven1 aBochud, Murielle1 aBoerwinkle, Eric1 aBojesen, Stig, E1 aBolla, Manjeet, K1 aBoomsma, Dorret, I1 aBowker, Nicholas1 aBrody, Jennifer, A1 aBroer, Linda1 aBuring, Julie, E1 aCampbell, Archie1 aCampbell, Harry1 aCastelao, Jose, E1 aCatamo, Eulalia1 aChanock, Stephen, J1 aChenevix-Trench, Georgia1 aCiullo, Marina1 aCorre, Tanguy1 aCouch, Fergus, J1 aCox, Angela1 aCrisponi, Laura1 aCross, Simon, S1 aCucca, Francesco1 aCzene, Kamila1 aSmith, George Davey1 ade Geus, Eco, J C N1 ade Mutsert, Renée1 aDe Vivo, Immaculata1 aDemerath, Ellen, W1 aDennis, Joe1 aDunning, Alison, M1 aDwek, Miriam1 aEriksson, Mikael1 aEsko, Tõnu1 aFasching, Peter, A1 aFaul, Jessica, D1 aFerrucci, Luigi1 aFranceschini, Nora1 aFrayling, Timothy, M1 aGago-Dominguez, Manuela1 aMezzavilla, Massimo1 aGarcía-Closas, Montserrat1 aGieger, Christian1 aGiles, Graham, G1 aGrallert, Harald1 aGudbjartsson, Daniel, F1 aGudnason, Vilmundur1 aGuénel, Pascal1 aHaiman, Christopher, A1 aHåkansson, Niclas1 aHall, Per1 aHayward, Caroline1 aHe, Chunyan1 aHe, Wei1 aHeiss, Gerardo1 aHøffding, Miya, K1 aHopper, John, L1 aHottenga, Jouke, J1 aHu, Frank1 aHunter, David1 aIkram, Mohammad, A1 aJackson, Rebecca, D1 aJoaquim, Micaella, D R1 aJohn, Esther, M1 aJoshi, Peter, K1 aKarasik, David1 aKardia, Sharon, L R1 aKartsonaki, Christiana1 aKarlsson, Robert1 aKitahara, Cari, M1 aKolcic, Ivana1 aKooperberg, Charles1 aKraft, Peter1 aKurian, Allison, W1 aKutalik, Zoltán1 aLa Bianca, Martina1 aLachance, Genevieve1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLaven, Joop, S E1 aLawlor, Deborah, A1 aLe Marchand, Loïc1 aLi, Jingmei1 aLindblom, Annika1 aLindström, Sara1 aLindstrom, Tricia1 aLinet, Martha1 aLiu, Yongmei1 aLiu, Simin1 aLuan, Jian'an1 aMägi, Reedik1 aMagnusson, Patrik, K E1 aMangino, Massimo1 aMannermaa, Arto1 aMarco, Brumat1 aMarten, Jonathan1 aMartin, Nicholas, G1 aMbarek, Hamdi1 aMcKnight, Barbara1 aMedland, Sarah, E1 aMeisinger, Christa1 aMeitinger, Thomas1 aMenni, Cristina1 aMetspalu, Andres1 aMilani, Lili1 aMilne, Roger, L1 aMontgomery, Grant, W1 aMook-Kanamori, Dennis, O1 aMulas, Antonella1 aMulligan, Anna, M1 aMurray, Alison1 aNalls, Mike, A1 aNewman, Anne1 aNoordam, Raymond1 aNutile, Teresa1 aNyholt, Dale, R1 aOlshan, Andrew, F1 aOlsson, Håkan1 aPainter, Jodie, N1 aPatel, Alpa, V1 aPedersen, Nancy, L1 aPerjakova, Natalia1 aPeters, Annette1 aPeters, Ulrike1 aPharoah, Paul, D P1 aPolasek, Ozren1 aPorcu, Eleonora1 aPsaty, Bruce, M1 aRahman, Iffat1 aRennert, Gad1 aRennert, Hedy, S1 aRidker, Paul, M1 aRing, Susan, M1 aRobino, Antonietta1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRossouw, Jacques1 aRudan, Igor1 aRueedi, Rico1 aRuggiero, Daniela1 aSala, Cinzia, F1 aSaloustros, Emmanouil1 aSandler, Dale, P1 aSanna, Serena1 aSawyer, Elinor, J1 aSarnowski, Chloe1 aSchlessinger, David1 aSchmidt, Marjanka, K1 aSchoemaker, Minouk, J1 aSchraut, Katharina, E1 aScott, Christopher1 aShekari, Saleh1 aShrikhande, Amruta1 aSmith, Albert, V1 aSmith, Blair, H1 aSmith, Jennifer, A1 aSorice, Rossella1 aSouthey, Melissa, C1 aSpector, Tim, D1 aSpinelli, John, J1 aStampfer, Meir1 aStöckl, Doris1 avan Meurs, Joyce, B J1 aStrauch, Konstantin1 aStyrkarsdottir, Unnur1 aSwerdlow, Anthony, J1 aTanaka, Toshiko1 aTeras, Lauren, R1 aTeumer, Alexander1 aÞorsteinsdottir, Unnur1 aTimpson, Nicholas, J1 aToniolo, Daniela1 aTraglia, Michela1 aTroester, Melissa, A1 aTruong, Thérèse1 aTyrrell, Jessica1 aUitterlinden, André, G1 aUlivi, Sheila1 aVachon, Celine, M1 aVitart, Veronique1 aVölker, Uwe1 aVollenweider, Peter1 aVölzke, Henry1 aWang, Qin1 aWareham, Nicholas, J1 aWeinberg, Clarice, R1 aWeir, David, R1 aWilcox, Amber, N1 aDijk, Ko Willems1 aWillemsen, Gonneke1 aWilson, James, F1 aWolffenbuttel, Bruce, H R1 aWolk, Alicja1 aWood, Andrew, R1 aZhao, Wei1 aZygmunt, Marek1 aChen, Zhengming1 aLi, Liming1 aFranke, Lude1 aBurgess, Stephen1 aDeelen, Patrick1 aPers, Tune, H1 aGrøndahl, Marie, Louise1 aAndersen, Claus, Yding1 aPujol, Anna1 aLopez-Contreras, Andres, J1 aDaniel, Jeremy, A1 aStefansson, Kari1 aChang-Claude, Jenny1 aSchouw, Yvonne, T1 aLunetta, Kathryn, L1 aChasman, Daniel, I1 aEaston, Douglas, F1 aVisser, Jenny, A1 aOzanne, Susan, E1 aNamekawa, Satoshi, H1 aSolc, Petr1 aMurabito, Joanne, M1 aOng, Ken, K1 aHoffmann, Eva, R1 aMurray, Anna1 aRoig, Ignasi1 aPerry, John, R B1 aBiobank-based Integrative Omics Study (BIOS) Consortium1 aeQTLGen Consortium1 aBioBank Japan Project1 aChina Kadoorie Biobank Collaborative Group1 akConFab Investigators1 aLifeLines Cohort Study1 aInterAct Consortium1 a23andMe Research Team uhttps://chs-nhlbi.org/node/8835