05167nas a2201273 4500008004100000022001400041245013800055210006900193260001300262300001300275490000700288520164300295653002201938653001201960653004901972653001902021653001402040653002502054653001102079653001702090653003402107653001102141653001702152653000902169653002202178653000902200653003102209653003602240100002002276700001502296700002802311700002202339700002102361700002302382700001802405700002302423700001802446700001902464700002102483700002402504700001702528700001502545700001802560700002302578700001502601700002202616700002102638700001602659700002402675700002002699700001402719700001402733700002002747700002302767700001702790700001702807700002302824700002502847700002402872700001702896700001802913700002202931700002402953700002002977700002202997700001303019700001403032700002403046700001803070700002103088700002003109700001803129700002103147700002203168700001903190700001703209700002803226700002003254700002103274700001803295700001903313700002103332700002403353700001503377700001603392700002003408700002403428700002303452700002103475700002103496700001703517700002003534700002003554700001903574700002403593700002103617700001603638700002103654700001903675700002303694700001403717700002203731700002003753700001703773700002603790700001803816700002303834856003603857 2017 eng d a1553-740400aSingle-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.0 aSingletrait and multitrait genomewide association analyses ident c2017 May ae10067280 v133 a
Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.
10aAfrican Americans10aAnimals10aBasic Helix-Loop-Helix Transcription Factors10aBlood Pressure10aCadherins10aCase-Control Studies10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aHypertension10aMale10aMembrane Proteins10aMice10aMultifactorial Inheritance10aPolymorphism, Single Nucleotide1 aLiang, Jingjing1 aLe, Thu, H1 aEdwards, Digna, R Velez1 aTayo, Bamidele, O1 aGaulton, Kyle, J1 aSmith, Jennifer, A1 aLu, Yingchang1 aJensen, Richard, A1 aChen, Guanjie1 aYanek, Lisa, R1 aSchwander, Karen1 aTajuddin, Salman, M1 aSofer, Tamar1 aKim, Wonji1 aKayima, James1 aMcKenzie, Colin, A1 aFox, Ervin1 aNalls, Michael, A1 aYoung, Hunter, J1 aSun, Yan, V1 aLane, Jacqueline, M1 aCechova, Sylvia1 aZhou, Jie1 aTang, Hua1 aFornage, Myriam1 aMusani, Solomon, K1 aWang, Heming1 aLee, Juyoung1 aAdeyemo, Adebowale1 aDreisbach, Albert, W1 aForrester, Terrence1 aChu, Pei-Lun1 aCappola, Anne1 aEvans, Michele, K1 aMorrison, Alanna, C1 aMartin, Lisa, W1 aWiggins, Kerri, L1 aHui, Qin1 aZhao, Wei1 aJackson, Rebecca, D1 aWare, Erin, B1 aFaul, Jessica, D1 aReiner, Alex, P1 aBray, Michael1 aDenny, Joshua, C1 aMosley, Thomas, H1 aPalmas, Walter1 aGuo, Xiuqing1 aPapanicolaou, George, J1 aPenman, Alan, D1 aPolak, Joseph, F1 aRice, Kenneth1 aTaylor, Ken, D1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aLiu, Kiang1 aRisch, Neil1 aHunt, Steven, C1 aKooperberg, Charles1 aZonderman, Alan, B1 aLaurie, Cathy, C1 aBecker, Diane, M1 aCai, Jianwen1 aLoos, Ruth, J F1 aPsaty, Bruce, M1 aWeir, David, R1 aKardia, Sharon, L R1 aArnett, Donna, K1 aWon, Sungho1 aEdwards, Todd, L1 aRedline, Susan1 aCooper, Richard, S1 aRao, D, C1 aRotter, Jerome, I1 aRotimi, Charles1 aLevy, Daniel1 aChakravarti, Aravinda1 aZhu, Xiaofeng1 aFranceschini, Nora uhttps://chs-nhlbi.org/node/757212060nas a2203745 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2018 eng d a1537-660500aA Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.0 aLargeScale Multiancestry Genomewide Study Accounting for Smoking c2018 Mar 01 a375-4000 v1023 aGenome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).
1 aSung, Yun, J1 aWinkler, Thomas, W1 aFuentes, Lisa, de Las1 aBentley, Amy, R1 aBrown, Michael, R1 aKraja, Aldi, T1 aSchwander, Karen1 aNtalla, Ioanna1 aGuo, Xiuqing1 aFranceschini, Nora1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aMarten, Jonathan1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aKilpeläinen, Tuomas, O1 aRichard, Melissa, A1 aNoordam, Raymond1 aAslibekyan, Stella1 aAschard, Hugues1 aBartz, Traci, M1 aDorajoo, Rajkumar1 aLiu, Yongmei1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, Vernon1 aTajuddin, Salman, M1 aTayo, Bamidele, O1 aWarren, Helen, R1 aZhao, Wei1 aZhou, Yanhua1 aMatoba, Nana1 aSofer, Tamar1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aGandin, Ilaria1 aGao, Chuan1 aGiulianini, Franco1 aGoel, Anuj1 aHarris, Sarah, E1 aHartwig, Fernando, Pires1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aJackson, Anne, U1 aKähönen, Mika1 aKasturiratne, Anuradhani1 aKuhnel, Brigitte1 aLeander, Karin1 aLee, Wen-Jane1 aLin, Keng-Hung1 aLuan, Jian, 'an1 aMcKenzie, Colin, A1 aMeian, He1 aNelson, Christopher, P1 aRauramaa, Rainer1 aSchupf, Nicole1 aScott, Robert, A1 aSheu, Wayne, H H1 aStančáková, Alena1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Heming1 aWang, Yajuan1 aWare, Erin, B1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAfaq, Saima1 aAlfred, Tamuno1 aAmin, Najaf1 aArking, Dan1 aAung, Tin1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBraund, Peter, S1 aBrody, Jennifer, A1 aBroeckel, Ulrich1 aCabrera, Claudia, P1 aCade, Brian1 aCaizheng, Yu1 aCampbell, Archie1 aCanouil, Mickaël1 aChakravarti, Aravinda1 aChauhan, Ganesh1 aChristensen, Kaare1 aCocca, Massimiliano1 aCollins, Francis, S1 aConnell, John, M1 ade Mutsert, Renée1 ade Silva, Janaka1 aDebette, Stephanie1 aDörr, Marcus1 aDuan, Qing1 aEaton, Charles, B1 aEhret, Georg1 aEvangelou, Evangelos1 aFaul, Jessica, D1 aFisher, Virginia, A1 aForouhi, Nita, G1 aFranco, Oscar, H1 aFriedlander, Yechiel1 aGao, He1 aGigante, Bruna1 aGraff, Misa1 aGu, Charles1 aGu, Dongfeng1 aGupta, Preeti1 aHagenaars, Saskia, P1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHofman, Albert1 aHoward, Barbara, V1 aHunt, Steven1 aIrvin, Marguerite, R1 aJia, Yucheng1 aJoehanes, Roby1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKaufman, Joel1 aKerrison, Nicola, D1 aKhor, Chiea, Chuen1 aKoh, Woon-Puay1 aKoistinen, Heikki, A1 aKomulainen, Pirjo1 aKooperberg, Charles1 aKrieger, Jose, E1 aKubo, Michiaki1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLim, Sing, Hui1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Jingmin1 aLiu, Kiang1 aLiu, Yeheng1 aLoh, Marie1 aLohman, Kurt, K1 aLong, Jirong1 aLouie, Tin1 aMägi, Reedik1 aMahajan, Anubha1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilani, Lili1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMosley, Thomas, H1 aMunson, Peter1 aMurray, Alison, D1 aNalls, Mike, A1 aNasri, Ubaydah1 aNorris, Jill, M1 aNorth, Kari1 aOgunniyi, Adesola1 aPadmanabhan, Sandosh1 aPalmas, Walter, R1 aPalmer, Nicholette, D1 aPankow, James, S1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aRaitakari, Olli, T1 aRenstrom, Frida1 aRice, Treva, K1 aRidker, Paul, M1 aRobino, Antonietta1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSabanayagam, Charumathi1 aSalako, Babatunde, L1 aSandow, Kevin1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSeshadri, Sudha1 aSever, Peter1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aUitterlinden, André, G1 aWaldenberger, Melanie1 aWang, Lihua1 aWang, Ya, X1 aBin Wei, Wen1 aWilliams, Christine1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYuan, Jian-Min1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aChen, Yii-Der Ida1 ade Faire, Ulf1 aDeary, Ian, J1 aEsko, Tõnu1 aFarrall, Martin1 aForrester, Terrence1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, Lessa1 aHung, Yi-Jen1 aJonas, Jost, B1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLehtimäki, Terho1 aLiang, Kae-Woei1 aMagnusson, Patrik, K E1 aNewman, Anne, B1 aOldehinkel, Albertine, J1 aPereira, Alexandre, C1 aRedline, Susan1 aRettig, Rainer1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZheng, Wei1 aKamatani, Yoichiro1 aLaurie, Cathy, C1 aBouchard, Claude1 aCooper, Richard, S1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aKritchevsky, Stephen, B1 aLevy, Daniel1 aO'Connell, Jeff, R1 aPsaty, Bruce, M1 avan Dam, Rob, M1 aSims, Mario1 aArnett, Donna, K1 aMook-Kanamori, Dennis, O1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aFornage, Myriam1 aRotimi, Charles, N1 aProvince, Michael, A1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aReiner, Alex, P1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aCaulfield, Mark, J1 aElliott, Paul1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aCupples, Adrienne, L1 aRao, Dabeeru, C1 aChasman, Daniel, I1 aCHARGE Neurology Working Group1 aCOGENT-Kidney Consortium1 aGIANT Consortium1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/768604205nas a2200877 4500008004100000022001400041245012500055210006900180260001300249300001200262490000700274520175300281100001402034700001902048700002202067700002302089700002302112700001702135700002402152700002502176700001802201700002002219700002002239700002302259700001502282700002102297700001602318700002802334700002002362700002202382700002002404700002102424700002202445700001902467700002102486700002402507700002002531700001902551700002002570700002002590700002202610700002002632700002802652700001902680700002102699700001902720700002202739700001402761700002202775700002002797700001902817700001502836700002002851700001802871700001902889700001702908700002002925700002202945700002502967700002302992700001903015700001703034700002003051700002003071700002003091700002003111700002103131700002403152700002103176700001803197700002303215700001803238700001603256700001903272856003603291 2018 eng d a1535-498900aMultiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.0 aMultiethnic MetaAnalysis Identifies RAI1 as a Possible Obstructi c2018 Mar a391-4010 v583 aObstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.
1 aChen, Han1 aCade, Brian, E1 aGleason, Kevin, J1 aBjonnes, Andrew, C1 aStilp, Adrienne, M1 aSofer, Tamar1 aConomos, Matthew, P1 aAncoli-Israel, Sonia1 aArens, Raanan1 aAzarbarzin, Ali1 aBell, Graeme, I1 aBelow, Jennifer, E1 aChun, Sung1 aEvans, Daniel, S1 aEwert, Ralf1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aHaba-Rubio, José1 aHagen, Erika, W1 aHeinzer, Raphael1 aHillman, David, R1 aJohnson, Craig1 aKutalik, Zoltán1 aLane, Jacqueline, M1 aLarkin, Emma, K1 aLee, Seung, Ku1 aLiang, Jingjing1 aLoredo, Jose, S1 aMukherjee, Sutapa1 aPalmer, Lyle, J1 aPapanicolaou, George, J1 aPenzel, Thomas1 aPeppard, Paul, E1 aPost, Wendy, S1 aRamos, Alberto, R1 aRice, Ken1 aRotter, Jerome, I1 aSands, Scott, A1 aShah, Neomi, A1 aShin, Chol1 aStone, Katie, L1 aStubbe, Beate1 aSul, Jae, Hoon1 aTafti, Mehdi1 aTaylor, Kent, D1 aTeumer, Alexander1 aThornton, Timothy, A1 aTranah, Gregory, J1 aWang, Chaolong1 aWang, Heming1 aWarby, Simon, C1 aWellman, Andrew1 aZee, Phyllis, C1 aHanis, Craig, L1 aLaurie, Cathy, C1 aGottlieb, Daniel, J1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aSunyaev, Shamil, R1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/767503584nas a2200649 4500008004100000022001400041245010200055210006900157260001500226300001200241490000700253520177200260100001702032700001902049700001702068700002002085700001402105700002402119700002302143700001802166700002502184700001902209700002302228700002402251700002102275700002002296700001702316700002002333700001302353700002002366700002002386700002202406700003002428700002502458700002002483700001802503700001902521700002002540700002302560700002002583700002002603700002102623700002402644700002102668700001402689700001902703700002202722700002302744700001702767700001602784700002202800700002102822700001802843700001902861700001802880856003602898 2019 eng d a1460-208300aAdmixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans.0 aAdmixture mapping identifies novel loci for obstructive sleep ap c2019 02 15 a675-6870 v283 aObstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2 < 90%] and a secondary trait (respiratory event duration) in a Hispanic/Latino American population study of 11 575 individuals with significant variation in ancestral background. Linear mixed models were performed using previously inferred African, European and Amerindian local genetic ancestry markers. Global African ancestry was associated with a lower AHI, higher SaO2 and shorter event duration. Admixture mapping analysis of the primary OSA traits identified local African ancestry at the chromosomal region 2q37 as genome-wide significantly associated with AHI (P < 5.7 × 10-5), and European and Amerindian ancestries at 18q21 suggestively associated with both AHI and percentage time SaO2 < 90% (P < 10-3). Follow-up joint ancestry-SNP association analyses identified novel variants in ferrochelatase (FECH), significantly associated with AHI and percentage time SaO2 < 90% after adjusting for multiple tests (P < 8 × 10-6). These signals contributed to the admixture mapping associations and were replicated in independent cohorts. In this first admixture mapping study of OSA, novel associations with variants in the iron/heme metabolism pathway suggest a role for iron in influencing respiratory traits underlying OSA.
1 aWang, Heming1 aCade, Brian, E1 aSofer, Tamar1 aSands, Scott, A1 aChen, Han1 aBrowning, Sharon, R1 aStilp, Adrienne, M1 aLouie, Tin, L1 aThornton, Timothy, A1 aJohnson, Craig1 aBelow, Jennifer, E1 aConomos, Matthew, P1 aEvans, Daniel, S1 aGharib, Sina, A1 aGuo, Xiuqing1 aWood, Alexis, C1 aMei, Hao1 aYaffe, Kristine1 aLoredo, Jose, S1 aRamos, Alberto, R1 aBarrett-Connor, Elizabeth1 aAncoli-Israel, Sonia1 aZee, Phyllis, C1 aArens, Raanan1 aShah, Neomi, A1 aTaylor, Kent, D1 aTranah, Gregory, J1 aStone, Katie, L1 aHanis, Craig, L1 aWilson, James, G1 aGottlieb, Daniel, J1 aPatel, Sanjay, R1 aRice, Ken1 aPost, Wendy, S1 aRotter, Jerome, I1 aSunyaev, Shamil, R1 aCai, Jianwen1 aLin, Xihong1 aPurcell, Shaun, M1 aLaurie, Cathy, C1 aSaxena, Richa1 aRedline, Susan1 aZhu, Xiaofeng uhttps://chs-nhlbi.org/node/804904619nas a2201021 4500008004100000022001400041245012900055210006900184260001200253300001300265490000700278520172700285653001502012653001002027653000902037653002202046653003802068653002602106653003402132653001102166653002902177653002202206653003402228653001502262653001102277653001202288653004202300653000902342653001602351653002602367653005002393653001102443653001902454653003602473653002802509653002602537653001002563653002602573653001602599100001902615700001402634700002302648700001502671700002502686700001802711700002202729700002302751700001702774700002402791700002102815700002802836700002002864700002202884700002402906700002202930700001902952700002202971700001502993700002003008700001303028700002203041700002103063700001903084700002203103700002203125700002103147700001403168700001903182700001703201700002003218700002503238700001703263700002003280700002003300700002003320700002003340700002203360700002003382700002303402700002103425700002303446700002103469700001803490700001803508700001603526700001903542856003603561 2019 eng d a1553-740400aAssociations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep.0 aAssociations of variants In the hexokinase 1 and interleukin 18 c2019 04 ae10077390 v153 aSleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCell Adhesion Molecules, Neuronal10aComputational Biology10aExtracellular Matrix Proteins10aFemale10aGene Regulatory Networks10aGenetic Variation10aGenome-Wide Association Study10aHexokinase10aHumans10aHypoxia10aInterleukin-18 Receptor alpha Subunit10aMale10aMiddle Aged10aNerve Tissue Proteins10aNLR Family, Pyrin Domain-Containing 3 Protein10aOxygen10aOxyhemoglobins10aPolymorphism, Single Nucleotide10aQuantitative Trait Loci10aSerine Endopeptidases10aSleep10aSleep Apnea Syndromes10aYoung Adult1 aCade, Brian, E1 aChen, Han1 aStilp, Adrienne, M1 aLouie, Tin1 aAncoli-Israel, Sonia1 aArens, Raanan1 aBarfield, Richard1 aBelow, Jennifer, E1 aCai, Jianwen1 aConomos, Matthew, P1 aEvans, Daniel, S1 aFrazier-Wood, Alexis, C1 aGharib, Sina, A1 aGleason, Kevin, J1 aGottlieb, Daniel, J1 aHillman, David, R1 aJohnson, Craig1 aLederer, David, J1 aLee, Jiwon1 aLoredo, Jose, S1 aMei, Hao1 aMukherjee, Sutapa1 aPatel, Sanjay, R1 aPost, Wendy, S1 aPurcell, Shaun, M1 aRamos, Alberto, R1 aReid, Kathryn, J1 aRice, Ken1 aShah, Neomi, A1 aSofer, Tamar1 aTaylor, Kent, D1 aThornton, Timothy, A1 aWang, Heming1 aYaffe, Kristine1 aZee, Phyllis, C1 aHanis, Craig, L1 aPalmer, Lyle, J1 aRotter, Jerome, I1 aStone, Katie, L1 aTranah, Gregory, J1 aWilson, James, G1 aSunyaev, Shamil, R1 aLaurie, Cathy, C1 aZhu, Xiaofeng1 aSaxena, Richa1 aLin, Xihong1 aRedline, Susan uhttps://chs-nhlbi.org/node/804403011nas a2200361 4500008004100000022001400041245015500055210006900210260001600279520191700295100002202212700001702234700001702251700002302268700002102291700001602312700002002328700002202348700002102370700001902391700001402410700002102424700001802445700002002463700001902483700002202502700001802524700001902542700001602561700001902577700001702596856003602613 2019 eng d a1550-910900aEpigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American-specific associations.0 aEpigenomewide association analysis of daytime sleepiness in the c2019 May 293 aSTUDY OBJECTIVES: Daytime sleepiness is a consequence of inadequate sleep, sleep-wake control disorder, or other medical conditions. Population variability in prevalence of daytime sleepiness is likely due to genetic and biological factors as well as social and environmental influences. DNA methylation (DNAm) potentially influences multiple health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS).
METHODS: We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 619) and the Cardiovascular Health Study (n = 483), with cross-study replication and meta-analysis. Genetic variants near ESS-associated DNAm were analyzed for methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.
RESULTS: In MESA only, we detected four DNAm-ESS associations: one across all race/ethnic groups; three in African-Americans (AA) only. Two of the MESA AA associations, in genes KCTD5 and RXRA, nominally replicated in CHS (p-value < 0.05). In the AA meta-analysis, we detected 14 DNAm-ESS associations (FDR q-value < 0.05, top association p-value = 4.26 × 10-8). Three DNAm sites mapped to genes (CPLX3, GFAP, and C7orf50) with biological relevance. We also found evidence for associations with DNAm sites in RAI1, a gene associated with sleep and circadian phenotypes. UK Biobank follow-up analyses detected SNPs in RAI1, RXRA, and CPLX3 with nominal sleepiness associations.
CONCLUSIONS: We identified methylation sites in multiple genes possibly implicated in daytime sleepiness. Most significant DNAm-ESS associations were specific to AA. Future work is needed to identify mechanisms driving ancestry-specific methylation effects.
1 aBarfield, Richard1 aWang, Heming1 aLiu, Yongmei1 aBrody, Jennifer, A1 aSwenson, Brenton1 aLi, Ruitong1 aBartz, Traci, M1 aSotoodehnia, Nona1 aChen, Yii-der, I1 aCade, Brian, E1 aChen, Han1 aPatel, Sanjay, R1 aZhu, Xiaofeng1 aGharib, Sina, A1 aJohnson, Craig1 aRotter, Jerome, I1 aSaxena, Richa1 aPurcell, Shaun1 aLin, Xihong1 aRedline, Susan1 aSofer, Tamar uhttps://chs-nhlbi.org/node/809611178nas a2203793 4500008004100000022001400041245013500055210006900190260001300259300001200272490000700284520073900291100002001030700001701050700002201067700002301089700001901112700001901131700002101150700002301171700001501194700001501209700001701224700001701241700001801258700002001276700001701296700002001313700002501333700002301358700001701381700002101398700002401419700002101443700001701464700001801481700002001499700002001519700002001539700002201559700002201581700002001603700002101623700002401644700001401668700002201682700001701704700002201721700002001743700001301763700001901776700002501795700001501820700001501835700002301850700002101873700002501894700001401919700002801933700001801961700001701979700002101996700002902017700002202046700002102068700001902089700001902108700001802127700002802145700001702173700001902190700001902209700001602228700001902244700002302263700001902286700001902305700002102324700001702345700002502362700002302387700002202410700002702432700002002459700002002479700001702499700001802516700001702534700002102551700001902572700001802591700001902609700002302628700001602651700001602667700001902683700001902702700002302721700001402744700002502758700001702783700002402800700002102824700002402845700002102869700001802890700001902908700002102927700002202948700002802970700002202998700002303020700002403043700002103067700002603088700002103114700002203135700001803157700001503175700002203190700002203212700002103234700002003255700002103275700002403296700002503320700001903345700001203364700002103376700002003397700001903417700002303436700001903459700001603478700002203494700002003516700002003536700001903556700002103575700002003596700001703616700001903633700001903652700002303671700002103694700002203715700002303737700002803760700001903788700001803807700002403825700002103849700002803870700001903898700002203917700001903939700002303958700002403981700002204005700002004027700001904047700001304066700002004079700001504099700001804114700001704132700001504149700001504164700002004179700001504199700001604214700001804230700002004248700002404268700002304292700002204315700002104337700002104358700001704379700002104396700002304417700002204440700002204462700001904484700002004503700002704523700001904550700002604569700002604595700002704621700002304648700002004671700002404691700001904715700001804734700002304752700002004775700002004795700001904815700002104834700002604855700001904881700002404900700001604924700002404940700002504964700002204989700001705011700001405028700002005042700001605062700002305078700002005101700001905121700002405140700002605164700002305190700001405213700002005227700001905247700002105266700002205287700002305309700002805332700002205360700002605382700001705408700001405425700001605439700001705455700002705472700002005499700002405519700001305543700001905556700001705575700001905592700001405611700002305625700002105648700002105669700002205690700002205712700002305734700001805757700001805775700001805793700001605811700002005827700002005847700002305867700002205890700002105912700002205933700002305955700002705978700002306005700002506028700001906053700002206072700001906094700002106113700001406134700002206148700002706170700002906197700002706226700002606253700002106279700001906300700002206319700001706341700001706358700001506375700002606390700001906416700001906435700002506454700001806479700001906497700003006516700001706546700002406563700001506587700002106602700002206623700002406645700002406669700001706693700002006710700002006730700002006750700002906770700002006799700002506819700002106844700001806865700002206883700002306905700001906928700002006947700002006967700002306987700002207010700001807032700002107050700002107071700001807092700002407110700002407134700002007158700002307178700002507201710002907226710002907255710004307284710002107327856003607348 2019 eng d a1546-171800aMulti-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.0 aMultiancestry genomewide genesmoking interaction study of 387272 c2019 Apr a636-6480 v513 aThe concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.
1 aBentley, Amy, R1 aSung, Yun, J1 aBrown, Michael, R1 aWinkler, Thomas, W1 aKraja, Aldi, T1 aNtalla, Ioanna1 aSchwander, Karen1 aChasman, Daniel, I1 aLim, Elise1 aDeng, Xuan1 aGuo, Xiuqing1 aLiu, Jingmin1 aLu, Yingchang1 aCheng, Ching-Yu1 aSim, Xueling1 aVojinovic, Dina1 aHuffman, Jennifer, E1 aMusani, Solomon, K1 aLi, Changwei1 aFeitosa, Mary, F1 aRichard, Melissa, A1 aNoordam, Raymond1 aBaker, Jenna1 aChen, Guanjie1 aAschard, Hugues1 aBartz, Traci, M1 aDing, Jingzhong1 aDorajoo, Rajkumar1 aManning, Alisa, K1 aRankinen, Tuomo1 aSmith, Albert, V1 aTajuddin, Salman, M1 aZhao, Wei1 aGraff, Mariaelisa1 aAlver, Maris1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGoel, Anuj1 aHagemeijer, Yanick1 aHarris, Sarah, E1 aHartwig, Fernando, P1 aHe, Meian1 aHorimoto, Andrea, R V R1 aHsu, Fang-Chi1 aHung, Yi-Jen1 aJackson, Anne, U1 aKasturiratne, Anuradhani1 aKomulainen, Pirjo1 aKuhnel, Brigitte1 aLeander, Karin1 aLin, Keng-Hung1 aLuan, Jian'an1 aLyytikäinen, Leo-Pekka1 aMatoba, Nana1 aNolte, Ilja, M1 aPietzner, Maik1 aPrins, Bram1 aRiaz, Muhammad1 aRobino, Antonietta1 aSaid, Abdullah1 aSchupf, Nicole1 aScott, Robert, A1 aSofer, Tamar1 aStančáková, Alena1 aTakeuchi, Fumihiko1 aTayo, Bamidele, O1 avan der Most, Peter, J1 aVarga, Tibor, V1 aWang, Tzung-Dau1 aWang, Yajuan1 aWare, Erin, B1 aWen, Wanqing1 aXiang, Yong-Bing1 aYanek, Lisa, R1 aZhang, Weihua1 aZhao, Jing Hua1 aAdeyemo, Adebowale1 aAfaq, Saima1 aAmin, Najaf1 aAmini, Marzyeh1 aArking, Dan, E1 aArzumanyan, Zorayr1 aAung, Tin1 aBallantyne, Christie1 aBarr, Graham1 aBielak, Lawrence, F1 aBoerwinkle, Eric1 aBottinger, Erwin, P1 aBroeckel, Ulrich1 aBrown, Morris1 aCade, Brian, E1 aCampbell, Archie1 aCanouil, Mickaël1 aCharumathi, Sabanayagam1 aChen, Yii-Der Ida1 aChristensen, Kaare1 aConcas, Maria, Pina1 aConnell, John, M1 aFuentes, Lisa, de Las1 ade Silva, Janaka1 ade Vries, Paul, S1 aDoumatey, Ayo1 aDuan, Qing1 aEaton, Charles, B1 aEppinga, Ruben, N1 aFaul, Jessica, D1 aFloyd, James, S1 aForouhi, Nita, G1 aForrester, Terrence1 aFriedlander, Yechiel1 aGandin, Ilaria1 aGao, He1 aGhanbari, Mohsen1 aGharib, Sina, A1 aGigante, Bruna1 aGiulianini, Franco1 aGrabe, Hans, J1 aGu, Charles1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHirata, Makoto1 aHixson, James, E1 aIkram, Arfan, M1 aJia, Yucheng1 aJoehanes, Roby1 aJohnson, Craig1 aJonas, Jost, Bruno1 aJustice, Anne, E1 aKatsuya, Tomohiro1 aKhor, Chiea, Chuen1 aKilpeläinen, Tuomas, O1 aKoh, Woon-Puay1 aKolcic, Ivana1 aKooperberg, Charles1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKubo, Michiaki1 aKuusisto, Johanna1 aLakka, Timo, A1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLehne, Benjamin1 aLewis, Cora, E1 aLi, Yize1 aLiang, Jingjing1 aLin, Shiow1 aLiu, Ching-Ti1 aLiu, Jianjun1 aLiu, Kiang1 aLoh, Marie1 aLohman, Kurt, K1 aLouie, Tin1 aLuzzi, Anna1 aMägi, Reedik1 aMahajan, Anubha1 aManichaikul, Ani, W1 aMcKenzie, Colin, A1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMilani, Lili1 aMohlke, Karen, L1 aMomozawa, Yukihide1 aMorris, Andrew, P1 aMurray, Alison, D1 aNalls, Mike, A1 aNauck, Matthias1 aNelson, Christopher, P1 aNorth, Kari, E1 aO'Connell, Jeffrey, R1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPoulter, Neil1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRenstrom, Frida1 aRice, Treva, K1 aRich, Stephen, S1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRosendaal, Frits, R1 aRudan, Igor1 aSchmidt, Carsten, O1 aSchreiner, Pamela, J1 aScott, William, R1 aSever, Peter1 aShi, Yuan1 aSidney, Stephen1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aStarr, John, M1 aStrauch, Konstantin1 aStringham, Heather, M1 aTan, Nicholas, Y Q1 aTang, Hua1 aTaylor, Kent, D1 aTeo, Yik, Ying1 aTham, Yih, Chung1 aTiemeier, Henning1 aTurner, Stephen, T1 aUitterlinden, André, G1 avan Heemst, Diana1 aWaldenberger, Melanie1 aWang, Heming1 aWang, Lan1 aWang, Lihua1 aBin Wei, Wen1 aWilliams, Christine, A1 aWilson, Gregory1 aWojczynski, Mary, K1 aYao, Jie1 aYoung, Kristin1 aYu, Caizheng1 aYuan, Jian-Min1 aZhou, Jie1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 aChambers, John, C1 aCooper, Richard, S1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFarrall, Martin1 aFranks, Paul, W1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aHorta, Bernardo, L1 aJuang, Jyh-Ming, Jimmy1 aKamatani, Yoichiro1 aKammerer, Candace, M1 aKato, Norihiro1 aKooner, Jaspal, S1 aLaakso, Markku1 aLaurie, Cathy, C1 aLee, I-Te1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aPereira, Alexandre, C1 aRauramaa, Rainer1 aRedline, Susan1 aSamani, Nilesh, J1 aScott, James1 aShu, Xiao-Ou1 aHarst, Pim1 aWagenknecht, Lynne, E1 aWang, Jun-Sing1 aWang, Ya, Xing1 aWareham, Nicholas, J1 aWatkins, Hugh1 aWeir, David, R1 aWickremasinghe, Ananda, R1 aWu, Tangchun1 aZeggini, Eleftheria1 aZheng, Wei1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPsaty, Bruce, M1 aRidker, Paul, M1 avan Dam, Rob, M1 aMook-Kanamori, Dennis, O1 aFornage, Myriam1 aProvince, Michael, A1 aKelly, Tanika, N1 aFox, Ervin, R1 aHayward, Caroline1 aDuijn, Cornelia, M1 aTai, Shyong, E1 aWong, Tien, Yin1 aLoos, Ruth, J F1 aFranceschini, Nora1 aRotter, Jerome, I1 aZhu, Xiaofeng1 aBierut, Laura, J1 aGauderman, James1 aRice, Kenneth1 aMunroe, Patricia, B1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aRotimi, Charles, N1 aCupples, Adrienne, L1 aCOGENT-Kidney Consortium1 aEPIC-InterAct Consortium1 aUnderstanding Society Scientific Group1 aLifelines Cohort uhttps://chs-nhlbi.org/node/800506391nas a2201909 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2019 eng d a2041-172300aMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.0 aMultiancestry sleepbySNP interaction analysis in 126926 individu c2019 Nov 12 a51210 v103 aBoth short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.
1 aNoordam, Raymond1 aBos, Maxime, M1 aWang, Heming1 aWinkler, Thomas, W1 aBentley, Amy, R1 aKilpeläinen, Tuomas, O1 ade Vries, Paul, S1 aSung, Yun, Ju1 aSchwander, Karen1 aCade, Brian, E1 aManning, Alisa1 aAschard, Hugues1 aBrown, Michael, R1 aChen, Han1 aFranceschini, Nora1 aMusani, Solomon, K1 aRichard, Melissa1 aVojinovic, Dina1 aAslibekyan, Stella1 aBartz, Traci, M1 aFuentes, Lisa, de Las1 aFeitosa, Mary1 aHorimoto, Andrea, R1 aIlkov, Marjan1 aKho, Minjung1 aKraja, Aldi1 aLi, Changwei1 aLim, Elise1 aLiu, Yongmei1 aMook-Kanamori, Dennis, O1 aRankinen, Tuomo1 aTajuddin, Salman, M1 avan der Spek, Ashley1 aWang, Zhe1 aMarten, Jonathan1 aLaville, Vincent1 aAlver, Maris1 aEvangelou, Evangelos1 aGraff, Maria, E1 aHe, Meian1 aKuhnel, Brigitte1 aLyytikäinen, Leo-Pekka1 aMarques-Vidal, Pedro1 aNolte, Ilja, M1 aPalmer, Nicholette, D1 aRauramaa, Rainer1 aShu, Xiao-Ou1 aSnieder, Harold1 aWeiss, Stefan1 aWen, Wanqing1 aYanek, Lisa, R1 aAdolfo, Correa1 aBallantyne, Christie1 aBielak, Larry1 aBiermasz, Nienke, R1 aBoerwinkle, Eric1 aDimou, Niki1 aEiriksdottir, Gudny1 aGao, Chuan1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aHaba-Rubio, José1 aHarris, Tamara, B1 aHeikkinen, Sami1 aHeinzer, Raphael1 aHixson, James, E1 aHomuth, Georg1 aIkram, Arfan, M1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aLee, Jiwon1 aLiu, Jingmin1 aLohman, Kurt, K1 aLuik, Annemarie, I1 aMägi, Reedik1 aMartin, Lisa, W1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aNalls, Mike, A1 aO'Connell, Jeff1 aPeters, Annette1 aPeyser, Patricia1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRensen, Patrick, C N1 aRice, Treva, K1 aRich, Stephen, S1 aRoenneberg, Till1 aRotter, Jerome, I1 aSchreiner, Pamela, J1 aShikany, James1 aSidney, Stephen, S1 aSims, Mario1 aSitlani, Colleen, M1 aSofer, Tamar1 aStrauch, Konstantin1 aSwertz, Morris, A1 aTaylor, Kent, D1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aVölzke, Henry1 aWaldenberger, Melanie1 aWallance, Robert, B1 aDijk, Ko Willems1 aYu, Caizheng1 aZonderman, Alan, B1 aBecker, Diane, M1 aElliott, Paul1 aEsko, Tõnu1 aGieger, Christian1 aGrabe, Hans, J1 aLakka, Timo, A1 aLehtimäki, Terho1 aNorth, Kari, E1 aPenninx, Brenda, W J H1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWu, Tangchun1 aXiang, Yong-Bing1 aZheng, Wei1 aArnett, Donna, K1 aBouchard, Claude1 aEvans, Michele, K1 aGudnason, Vilmundur1 aKardia, Sharon1 aKelly, Tanika, N1 aKritchevsky, Stephen, B1 aLoos, Ruth, J F1 aPereira, Alexandre, C1 aProvince, Mike1 aPsaty, Bruce, M1 aRotimi, Charles1 aZhu, Xiaofeng1 aAmin, Najaf1 aCupples, Adrienne, L1 aFornage, Myriam1 aFox, Ervin, F1 aGuo, Xiuqing1 aGauderman, James1 aRice, Kenneth1 aKooperberg, Charles1 aMunroe, Patricia, B1 aLiu, Ching-Ti1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 avan Heemst, Diana1 aRedline, Susan uhttps://chs-nhlbi.org/node/820210097nas a2203265 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2019 eng d a2041-172300aMulti-ancestry study of blood lipid levels identifies four loci interacting with physical activity.0 aMultiancestry study of blood lipid levels identifies four loci i c2019 01 22 a3760 v103 aMany genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
10aAdolescent10aAdult10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aAsian Continental Ancestry Group10aBrazil10aCalcium-Binding Proteins10aCholesterol10aCholesterol, HDL10aCholesterol, LDL10aEuropean Continental Ancestry Group10aExercise10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHispanic Americans10aHumans10aLIM-Homeodomain Proteins10aLipid Metabolism10aLipids10aMale10aMembrane Proteins10aMicrotubule-Associated Proteins10aMiddle Aged10aMuscle Proteins10aNerve Tissue Proteins10aTranscription Factors10aTriglycerides10aYoung Adult1 aKilpeläinen, Tuomas, O1 aBentley, Amy, R1 aNoordam, Raymond1 aSung, Yun, Ju1 aSchwander, Karen1 aWinkler, Thomas, W1 aJakupović, Hermina1 aChasman, Daniel, I1 aManning, Alisa1 aNtalla, Ioanna1 aAschard, Hugues1 aBrown, Michael, R1 aFuentes, Lisa, de Las1 aFranceschini, Nora1 aGuo, Xiuqing1 aVojinovic, Dina1 aAslibekyan, Stella1 aFeitosa, Mary, F1 aKho, Minjung1 aMusani, Solomon, K1 aRichard, Melissa1 aWang, Heming1 aWang, Zhe1 aBartz, Traci, M1 aBielak, Lawrence, F1 aCampbell, Archie1 aDorajoo, Rajkumar1 aFisher, Virginia1 aHartwig, Fernando, P1 aHorimoto, Andrea, R V R1 aLi, Changwei1 aLohman, Kurt, K1 aMarten, Jonathan1 aSim, Xueling1 aSmith, Albert, V1 aTajuddin, Salman, M1 aAlver, Maris1 aAmini, Marzyeh1 aBoissel, Mathilde1 aChai, Jin, Fang1 aChen, Xu1 aDivers, Jasmin1 aEvangelou, Evangelos1 aGao, Chuan1 aGraff, Mariaelisa1 aHarris, Sarah, E1 aHe, Meian1 aHsu, Fang-Chi1 aJackson, Anne, U1 aZhao, Jing Hua1 aKraja, Aldi, T1 aKuhnel, Brigitte1 aLaguzzi, Federica1 aLyytikäinen, Leo-Pekka1 aNolte, Ilja, M1 aRauramaa, Rainer1 aRiaz, Muhammad1 aRobino, Antonietta1 aRueedi, Rico1 aStringham, Heather, M1 aTakeuchi, Fumihiko1 avan der Most, Peter, J1 aVarga, Tibor, V1 aVerweij, Niek1 aWare, Erin, B1 aWen, Wanqing1 aLi, Xiaoyin1 aYanek, Lisa, R1 aAmin, Najaf1 aArnett, Donna, K1 aBoerwinkle, Eric1 aBrumat, Marco1 aCade, Brian1 aCanouil, Mickaël1 aChen, Yii-Der Ida1 aConcas, Maria, Pina1 aConnell, John1 ade Mutsert, Renée1 ade Silva, Janaka1 ade Vries, Paul, S1 aDemirkan, Ayse1 aDing, Jingzhong1 aEaton, Charles, B1 aFaul, Jessica, D1 aFriedlander, Yechiel1 aGabriel, Kelley, P1 aGhanbari, Mohsen1 aGiulianini, Franco1 aGu, Chi, Charles1 aGu, Dongfeng1 aHarris, Tamara, B1 aHe, Jiang1 aHeikkinen, Sami1 aHeng, Chew-Kiat1 aHunt, Steven, C1 aIkram, Arfan, M1 aJonas, Jost, B1 aKoh, Woon-Puay1 aKomulainen, Pirjo1 aKrieger, Jose, E1 aKritchevsky, Stephen, B1 aKutalik, Zoltán1 aKuusisto, Johanna1 aLangefeld, Carl, D1 aLangenberg, Claudia1 aLauner, Lenore, J1 aLeander, Karin1 aLemaitre, Rozenn, N1 aLewis, Cora, E1 aLiang, Jingjing1 aLiu, Jianjun1 aMägi, Reedik1 aManichaikul, Ani1 aMeitinger, Thomas1 aMetspalu, Andres1 aMilaneschi, Yuri1 aMohlke, Karen, L1 aMosley, Thomas, H1 aMurray, Alison, D1 aNalls, Mike, A1 aNang, Ei-Ei, Khaing1 aNelson, Christopher, P1 aNona, Sotoodehnia1 aNorris, Jill, M1 aNwuba, Chiamaka, Vivian1 aO'Connell, Jeff1 aPalmer, Nicholette, D1 aPapanicolau, George, J1 aPazoki, Raha1 aPedersen, Nancy, L1 aPeters, Annette1 aPeyser, Patricia, A1 aPolasek, Ozren1 aPorteous, David, J1 aPoveda, Alaitz1 aRaitakari, Olli, T1 aRich, Stephen, S1 aRisch, Neil1 aRobinson, Jennifer, G1 aRose, Lynda, M1 aRudan, Igor1 aSchreiner, Pamela, J1 aScott, Robert, A1 aSidney, Stephen, S1 aSims, Mario1 aSmith, Jennifer, A1 aSnieder, Harold1 aSofer, Tamar1 aStarr, John, M1 aSternfeld, Barbara1 aStrauch, Konstantin1 aTang, Hua1 aTaylor, Kent, D1 aTsai, Michael, Y1 aTuomilehto, Jaakko1 aUitterlinden, André, G1 avan der Ende, Yldau1 avan Heemst, Diana1 aVoortman, Trudy1 aWaldenberger, Melanie1 aWennberg, Patrik1 aWilson, Gregory1 aXiang, Yong-Bing1 aYao, Jie1 aYu, Caizheng1 aYuan, Jian-Min1 aZhao, Wei1 aZonderman, Alan, B1 aBecker, Diane, M1 aBoehnke, Michael1 aBowden, Donald, W1 ade Faire, Ulf1 aDeary, Ian, J1 aElliott, Paul1 aEsko, Tõnu1 aFreedman, Barry, I1 aFroguel, Philippe1 aGasparini, Paolo1 aGieger, Christian1 aKato, Norihiro1 aLaakso, Markku1 aLakka, Timo, A1 aLehtimäki, Terho1 aMagnusson, Patrik, K E1 aOldehinkel, Albertine, J1 aPenninx, Brenda, W J H1 aSamani, Nilesh, J1 aShu, Xiao-Ou1 aHarst, Pim1 avan Vliet-Ostaptchouk, Jana, V1 aVollenweider, Peter1 aWagenknecht, Lynne, E1 aWang, Ya, X1 aWareham, Nicholas, J1 aWeir, David, R1 aWu, Tangchun1 aZheng, Wei1 aZhu, Xiaofeng1 aEvans, Michele, K1 aFranks, Paul, W1 aGudnason, Vilmundur1 aHayward, Caroline1 aHorta, Bernardo, L1 aKelly, Tanika, N1 aLiu, Yongmei1 aNorth, Kari, E1 aPereira, Alexandre, C1 aRidker, Paul, M1 aTai, Shyong, E1 avan Dam, Rob, M1 aFox, Ervin, R1 aKardia, Sharon, L R1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aRedline, Susan1 aDuijn, Cornelia, M1 aRotter, Jerome, I1 aKooperberg, Charles, B1 aGauderman, James1 aPsaty, Bruce, M1 aRice, Kenneth1 aMunroe, Patricia, B1 aFornage, Myriam1 aCupples, Adrienne, L1 aRotimi, Charles, N1 aMorrison, Alanna, C1 aRao, Dabeeru, C1 aLoos, Ruth, J F1 aLifeLines Cohort Study uhttps://chs-nhlbi.org/node/797603253nas a2200637 4500008004100000022001400041245013600055210006900191260001600260300001400276490000800290520140100298100002001699700001901719700001701738700001701755700001501772700001701787700002401804700001601828700001401844700002401858700002101882700001701903700002001920700001701940700002201957700002201979700002202001700002802023700002002051700002002071700001902091700002102110700001802131700002002149700001802169700002302187700002102210700001602231700001702247700002002264700002702284700002002311700002102331700002402352700001702376700002102393700002202414700002102436700001902457700001802476710005402494710003102548856003602579 2019 eng d a1537-660500aSequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level.0 aSequencing Analysis at 8p23 Identifies Multiple Rare Variants in c2019 Nov 07 a1057-10680 v1053 aAverage arterial oxyhemoglobin saturation during sleep (AvSpOS) is a clinically relevant measure of physiological stress associated with sleep-disordered breathing, and this measure predicts incident cardiovascular disease and mortality. Using high-depth whole-genome sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) project and focusing on genes with linkage evidence on chromosome 8p23, we observed that six coding and 51 noncoding variants in a gene that encodes the GTPase-activating protein (DLC1) are significantly associated with AvSpOS and replicated in independent subjects. The combined DLC1 association evidence of discovery and replication cohorts reaches genome-wide significance in European Americans (p = 7.9 × 10). A risk score for these variants, built on an independent dataset, explains 0.97% of the AvSpOS variation and contributes to the linkage evidence. The 51 noncoding variants are enriched in regulatory features in a human lung fibroblast cell line and contribute to DLC1 expression variation. Mendelian randomization analysis using these variants indicates a significant causal effect of DLC1 expression in fibroblasts on AvSpOS. Multiple sources of information, including genetic variants, gene expression, and methylation, consistently suggest that DLC1 is a gene associated with AvSpOS.
1 aLiang, Jingjing1 aCade, Brian, E1 aHe, Karen, Y1 aWang, Heming1 aLee, Jiwon1 aSofer, Tamar1 aWilliams, Stephanie1 aLi, Ruitong1 aChen, Han1 aGottlieb, Daniel, J1 aEvans, Daniel, S1 aGuo, Xiuqing1 aGharib, Sina, A1 aHale, Lauren1 aHillman, David, R1 aLutsey, Pamela, L1 aMukherjee, Sutapa1 aOchs-Balcom, Heather, M1 aPalmer, Lyle, J1 aRhodes, Jessica1 aPurcell, Shaun1 aPatel, Sanjay, R1 aSaxena, Richa1 aStone, Katie, L1 aTang, Weihong1 aTranah, Gregory, J1 aBoerwinkle, Eric1 aLin, Xihong1 aLiu, Yongmei1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aCho, Michael, H1 aManichaikul, Ani1 aSilverman, Edwin, K1 aBarr, Graham1 aRich, Stephen, S1 aRotter, Jerome, I1 aWilson, James, G1 aRedline, Susan1 aZhu, Xiaofeng1 aNHLBI Trans-Omics for Precision Medicine (TOPMed)1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/819903741nas a2200625 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520194400253100001402197700001402211700002002225700002402245700002302269700002102292700002302313700001702336700001502353700002102368700002402389700001702413700001602430700002502446700002202471700002202493700001502515700002402530700002002554700002002574700002102594700002502615700002002640700002402660700002302684700002602707700001302733700001402746700002002760700002402780700002402804700001802828700002902846700002502875700002002900700001902920700002002939700002202959700002102981700002403002710005303026856003603079 2020 eng d a2574-830000aRole of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.0 aRole of Rare and LowFrequency Variants in GeneAlcohol Interactio c2020 Aug ae0027720 v133 aBACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.
METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.
RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .
CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.
1 aWang, Zhe1 aChen, Han1 aBartz, Traci, M1 aBielak, Lawrence, F1 aChasman, Daniel, I1 aFeitosa, Mary, F1 aFranceschini, Nora1 aGuo, Xiuqing1 aLim, Elise1 aNoordam, Raymond1 aRichard, Melissa, A1 aWang, Heming1 aCade, Brian1 aCupples, Adrienne, L1 ade Vries, Paul, S1 aGiulanini, Franco1 aLee, Jiwon1 aLemaitre, Rozenn, N1 aMartin, Lisa, W1 aReiner, Alex, P1 aRich, Stephen, S1 aSchreiner, Pamela, J1 aSidney, Stephen1 aSitlani, Colleen, M1 aSmith, Jennifer, A1 avan Dijk, Ko, Willems1 aYao, Jie1 aZhao, Wei1 aFornage, Myriam1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Ching-Ti1 aMook-Kanamori, Dennis, O1 aProvince, Michael, A1 aPsaty, Bruce, M1 aRedline, Susan1 aRidker, Paul, M1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aMorrison, Alanna, C1 aCHARGE Gene-Lifestyle Interactions Working Group uhttps://chs-nhlbi.org/node/840706233nas a2201609 4500008004100000022001400041245009500055210006900150260001600219520178500235100001702020700002102037700001902058700002102077700002302098700001502121700001802136700002002154700002202174700002002196700002802216700001802244700002202262700002402284700002102308700002002329700002002349700001502369700002502384700001702409700003102426700002002457700002302477700002302500700002102523700001702544700002002561700002102581700002702602700001902629700002402648700002602672700002102698700001802719700001702737700001902754700002802773700002002801700002402821700002202845700002202867700001902889700001402908700002102922700002102943700002502964700002002989700002203009700001803031700002203049700002003071700001903091700002303110700002003133700002803153700001603181700001503197700001703212700001403229700002003243700002303263700001903286700001603305700002003321700001703341700002103358700001903379700001303398700001703411700002203428700002403450700002903474700002003503700001503523700002303538700002403561700002203585700002003607700001803627700001703645700002103662700001903683700002103702700001603723700001503739700002603754700002003780700002403800700002203824700002103846700001703867700001803884700001703902700002203919700002203941700002003963700002603983700002204009700001904031700001504050700002004065700002204085700002404107700002404131700002604155700002004181700002004201700002304221700001804244700002104262700002204283700002104305700001804326700002404344700001804368700001904386700001604405700001904421700001804440700002004458700002704478700002104505700002004526700001904546700002204565856003604587 2021 eng d a1476-557800aMulti-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.0 aMultiancestry genomewide genesleep interactions identify novel l c2021 Apr 153 aLong and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 × 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 × 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 × 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.
1 aWang, Heming1 aNoordam, Raymond1 aCade, Brian, E1 aSchwander, Karen1 aWinkler, Thomas, W1 aLee, Jiwon1 aSung, Yun, Ju1 aBentley, Amy, R1 aManning, Alisa, K1 aAschard, Hugues1 aKilpeläinen, Tuomas, O1 aIlkov, Marjan1 aBrown, Michael, R1 aHorimoto, Andrea, R1 aRichard, Melissa1 aBartz, Traci, M1 aVojinovic, Dina1 aLim, Elise1 aNierenberg, Jovia, L1 aLiu, Yongmei1 aChitrala, Kumaraswamynaidu1 aRankinen, Tuomo1 aMusani, Solomon, K1 aFranceschini, Nora1 aRauramaa, Rainer1 aAlver, Maris1 aZee, Phyllis, C1 aHarris, Sarah, E1 avan der Most, Peter, J1 aNolte, Ilja, M1 aMunroe, Patricia, B1 aPalmer, Nicholette, D1 aKuhnel, Brigitte1 aWeiss, Stefan1 aWen, Wanqing1 aHall, Kelly, A1 aLyytikäinen, Leo-Pekka1 aO'Connell, Jeff1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 ade Vries, Paul, S1 aArking, Dan, E1 aChen, Han1 aBoerwinkle, Eric1 aKrieger, Jose, E1 aSchreiner, Pamela, J1 aSidney, Stephen1 aShikany, James, M1 aRice, Kenneth1 aChen, Yii-Der Ida1 aGharib, Sina, A1 aBis, Joshua, C1 aLuik, Annemarie, I1 aIkram, Arfan, M1 aUitterlinden, André, G1 aAmin, Najaf1 aXu, Hanfei1 aLevy, Daniel1 aHe, Jiang1 aLohman, Kurt, K1 aZonderman, Alan, B1 aRice, Treva, K1 aSims, Mario1 aWilson, Gregory1 aSofer, Tamar1 aRich, Stephen, S1 aPalmas, Walter1 aYao, Jie1 aGuo, Xiuqing1 aRotter, Jerome, I1 aBiermasz, Nienke, R1 aMook-Kanamori, Dennis, O1 aMartin, Lisa, W1 aBarac, Ana1 aWallace, Robert, B1 aGottlieb, Daniel, J1 aKomulainen, Pirjo1 aHeikkinen, Sami1 aMägi, Reedik1 aMilani, Lili1 aMetspalu, Andres1 aStarr, John, M1 aMilaneschi, Yuri1 aWaken, R, J1 aGao, Chuan1 aWaldenberger, Melanie1 aPeters, Annette1 aStrauch, Konstantin1 aMeitinger, Thomas1 aRoenneberg, Till1 aVölker, Uwe1 aDörr, Marcus1 aShu, Xiao-Ou1 aMukherjee, Sutapa1 aHillman, David, R1 aKähönen, Mika1 aWagenknecht, Lynne, E1 aGieger, Christian1 aGrabe, Hans, J1 aZheng, Wei1 aPalmer, Lyle, J1 aLehtimäki, Terho1 aGudnason, Vilmundur1 aMorrison, Alanna, C1 aPereira, Alexandre, C1 aFornage, Myriam1 aPsaty, Bruce, M1 aDuijn, Cornelia, M1 aLiu, Ching-Ti1 aKelly, Tanika, N1 aEvans, Michele, K1 aBouchard, Claude1 aFox, Ervin, R1 aKooperberg, Charles1 aZhu, Xiaofeng1 aLakka, Timo, A1 aEsko, Tõnu1 aNorth, Kari, E1 aDeary, Ian, J1 aSnieder, Harold1 aPenninx, Brenda, W J H1 aGauderman, James1 aRao, Dabeeru, C1 aRedline, Susan1 avan Heemst, Diana uhttps://chs-nhlbi.org/node/871403828nas a2200625 4500008004100000022001400041245010800055210006900163260001500232300000800247490000700255520201900262100001902281700001502300700001702315700001702332700001502349700001402364700002002378700002402398700001702422700002402439700002002463700001602483700001302499700002102512700002202533700001802555700001902573700002102592700002002613700002202633700002202655700002002677700002002697700002302717700002502740700002402765700001902789700002502808700002202833700002602855700001902881700002002900700002202920700002102942700002202963700002702985700002103012700001803033700001903051710006503070710003103135856003603166 2021 eng d a1756-994X00aWhole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program.0 aWholegenome association analyses of sleepdisordered breathing ph c2021 08 26 a1360 v133 aBACKGROUND: Sleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.
METHODS: The study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation < 90%. We adjusted for age, sex, BMI, study, and family structure using MMSKAT and EMMAX mixed linear model approaches. Additional bioinformatics analyses were performed with MetaXcan, GIGSEA, and ReMap.
RESULTS: We identified a multi-ethnic set-based rare-variant association (p = 3.48 × 10) on chromosome X with ARMCX3. Additional rare-variant associations include ARMCX3-AS1, MRPS33, and C16orf90. Novel common-variant loci were identified in the NRG1 and SLC45A2 regions, and previously associated loci in the IL18RAP and ATP2B4 regions were associated with novel phenotypes. Transcription factor binding site enrichment identified associations with genes implicated with respiratory and craniofacial traits. Additional analyses identified significantly associated pathways.
CONCLUSIONS: We have identified the first gene-based rare-variant associations with objectively measured sleep-disordered breathing traits. Our results increase the understanding of the genetic architecture of sleep-disordered breathing and highlight associations in genes that modulate lung development, inflammation, respiratory rhythmogenesis, and HIF1A-mediated hypoxic response.
1 aCade, Brian, E1 aLee, Jiwon1 aSofer, Tamar1 aWang, Heming1 aZhang, Man1 aChen, Han1 aGharib, Sina, A1 aGottlieb, Daniel, J1 aGuo, Xiuqing1 aLane, Jacqueline, M1 aLiang, Jingjing1 aLin, Xihong1 aMei, Hao1 aPatel, Sanjay, R1 aPurcell, Shaun, M1 aSaxena, Richa1 aShah, Neomi, A1 aEvans, Daniel, S1 aHanis, Craig, L1 aHillman, David, R1 aMukherjee, Sutapa1 aPalmer, Lyle, J1 aStone, Katie, L1 aTranah, Gregory, J1 aAbecasis, Goncalo, R1 aBoerwinkle, Eric, A1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aKaplan, Robert, C1 aNickerson, Deborah, A1 aNorth, Kari, E1 aPsaty, Bruce, M1 aRotter, Jerome, I1 aRich, Stephen, S1 aTracy, Russell, P1 aVasan, Ramachandran, S1 aWilson, James, G1 aZhu, Xiaofeng1 aRedline, Susan1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/892003348nas a2200541 4500008004100000022001400041245012000055210006900175260001600244520177900260100002002039700001702059700001902076700002502095700001702120700001502137700002002152700002002172700001402192700002402206700002102230700001702251700002002268700001702288700002202305700002202327700002202349700002802371700002002399700001902419700001802438700002102456700002002477700002302497700002102520700001602541700001702557700002002574700002702594700002102621700002102642700002202663700001702685700001902702700001802721710003102739856003602770 2022 eng d a1535-497000aTargeted Genome Sequencing Identifies Multiple Rare Variants in Caveolin-1 Associated with Obstructive Sleep Apnea.0 aTargeted Genome Sequencing Identifies Multiple Rare Variants in c2022 Jul 133 aINTRODUCTION: Obstructive sleep apnea (OSA) is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. There is strong clinical and epi-demiologic evidence supporting the importance of genetic factors influencing OSA, but limited data implicating specific genes.
METHODS: Leveraging high depth genomic sequencing data from the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and imputed genotype data from multiple population-based studies, we performed linkage analysis in the Cleve-land Family Study (CFS) followed by multi-stage gene-based association analyses in independent cohorts to search for rare variants contributing to OSA severity as assessed by the apnea-hypopnea index (AHI) in a total of 7,708 individuals of European ancestry.
RESULTS: Linkage analysis in CFS identified a suggestive linkage peak on chromosome 7q31 (LOD=2.31). Gene-based analysis identified 21 non-coding rare variants in Caveolin-1 (CAV1) associated with lower AHI after accounting for multiple comparisons (p=7.4×10-8). These non-coding variants together significantly contributed to the linkage evidence (p<10-3). Follow-up anal-ysis revealed significant associations between these variants and increased CAV1 expression, and increased CAV1 expression in peripheral monocytes was associated with lower AHI (p=0.024) and higher minimum overnight oxygen saturation (p=0.007).
CONCLUSION: Rare variants in CAV1, a membrane scaffolding protein essential in multiple cellular and metabolic functions, are associated with higher CAV1 gene expression and lower OSA severity, suggesting a novel target for modulating OSA severity.
1 aLiang, Jingjing1 aWang, Heming1 aCade, Brian, E1 aKurniansyah, Nuzulul1 aHe, Karen, Y1 aLee, Jiwon1 aSands, Scott, A1 aBrody, Jennifer1 aChen, Han1 aGottlieb, Daniel, J1 aEvans, Daniel, S1 aGuo, Xiuqing1 aGharib, Sina, A1 aHale, Lauren1 aHillman, David, R1 aLutsey, Pamela, L1 aMukherjee, Sutapa1 aOchs-Balcom, Heather, M1 aPalmer, Lyle, J1 aPurcell, Shaun1 aSaxena, Richa1 aPatel, Sanjay, R1 aStone, Katie, L1 aTranah, Gregory, J1 aBoerwinkle, Eric1 aLin, Xihong1 aLiu, Yongmei1 aPsaty, Bruce, M1 aVasan, Ramachandran, S1 aManichaikul, Ani1 aRich, Stephen, S1 aRotter, Jerome, I1 aSofer, Tamar1 aRedline, Susan1 aZhu, Xiaofeng1 aTOPMed Sleep Working Group uhttps://chs-nhlbi.org/node/910105141nas a2201381 4500008004100000022001400041245014300055210006900198260001500267300000800282490000600290520117000296653003001466653001201496653001201508653001101520653001201531653005301543653002601596653003601622653002301658653002701681653001801708100002001726700002201746700002201768700002601790700002301816700002501839700001501864700002101879700002501900700001801925700002401943700002201967700002301989700002002012700001702032700002002049700002602069700001902095700002202114700001902136700001702155700001702172700003302189700002102222700001902243700001802262700002602280700002002306700002102326700002302347700002602370700002202396700002402418700002302442700002202465700002002487700002202507700002002529700002502549700002102574700002102595700001802616700001802634700002002652700002102672700002102693700001702714700002102731700003102752700002502783700003402808700002202842700002302864700002102887700001602908700001302924700001402937700002002951700001902971700002102990700001903011700002103030700001903051700002503070700002203095700002803117700001403145700002303159700002403182700001703206700002403223700001503247700002303262700002503285700002503310700002403335700002403359700002003383700001903403700002303422700002003445700002703465700003003492700002003522700002103542700001903563700002103582700002203603700001603625700001903641700002003660700002103680700002203701856003603723 2022 eng d a2399-364200aWhole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.0 aWhole genome sequence association analysis of fasting glucose an c2022 07 28 a7560 v53 aThe genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.
10aDiabetes Mellitus, Type 210aFasting10aGlucose10aHumans10aInsulin10aNational Heart, Lung, and Blood Institute (U.S.)10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aPrecision Medicine10aReceptors, Immunologic10aUnited States1 aDiCorpo, Daniel1 aGaynor, Sheila, M1 aRussell, Emily, M1 aWesterman, Kenneth, E1 aRaffield, Laura, M1 aMajarian, Timothy, D1 aWu, Peitao1 aSarnowski, Chloe1 aHighland, Heather, M1 aJackson, Anne1 aHasbani, Natalie, R1 ade Vries, Paul, S1 aBrody, Jennifer, A1 aHidalgo, Bertha1 aGuo, Xiuqing1 aPerry, James, A1 aO'Connell, Jeffrey, R1 aLent, Samantha1 aMontasser, May, E1 aCade, Brian, E1 aJain, Deepti1 aWang, Heming1 aAlbanus, Ricardo, D'Oliveira1 aVarshney, Arushi1 aYanek, Lisa, R1 aLange, Leslie1 aPalmer, Nicholette, D1 aAlmeida, Marcio1 aPeralta, Juan, M1 aAslibekyan, Stella1 aBaldridge, Abigail, S1 aBertoni, Alain, G1 aBielak, Lawrence, F1 aChen, Chung-Shiuan1 aChen, Yii-Der Ida1 aChoi, Won, Jung1 aGoodarzi, Mark, O1 aFloyd, James, S1 aIrvin, Marguerite, R1 aKalyani, Rita, R1 aKelly, Tanika, N1 aLee, Seonwook1 aLiu, Ching-Ti1 aLoesch, Douglas1 aManson, JoAnn, E1 aMinster, Ryan, L1 aNaseri, Take1 aPankow, James, S1 aRasmussen-Torvik, Laura, J1 aReiner, Alexander, P1 aReupena, Muagututi'a, Sefuiva1 aSelvin, Elizabeth1 aSmith, Jennifer, A1 aWeeks, Daniel, E1 aXu, Huichun1 aYao, Jie1 aZhao, Wei1 aParker, Stephen1 aAlonso, Alvaro1 aArnett, Donna, K1 aBlangero, John1 aBoerwinkle, Eric1 aCorrea, Adolfo1 aCupples, Adrienne, L1 aCurran, Joanne, E1 aDuggirala, Ravindranath1 aHe, Jiang1 aHeckbert, Susan, R1 aKardia, Sharon, L R1 aKim, Ryan, W1 aKooperberg, Charles1 aLiu, Simin1 aMathias, Rasika, A1 aMcGarvey, Stephen, T1 aMitchell, Braxton, D1 aMorrison, Alanna, C1 aPeyser, Patricia, A1 aPsaty, Bruce, M1 aRedline, Susan1 aShuldiner, Alan, R1 aTaylor, Kent, D1 aVasan, Ramachandran, S1 aViaud-Martinez, Karine, A1 aFlorez, Jose, C1 aWilson, James, G1 aSladek, Robert1 aRich, Stephen, S1 aRotter, Jerome, I1 aLin, Xihong1 aDupuis, Josée1 aMeigs, James, B1 aWessel, Jennifer1 aManning, Alisa, K uhttps://chs-nhlbi.org/node/915807212nas a2201753 4500008004100000245012700041210006900168260001600237520220800253100002502461700001902486700001602505700001902521700002302540700001902563700002302582700002102605700001802626700002002644700002402664700002302688700002902711700002302740700002002763700002102783700002102804700002102825700002402846700002202870700001902892700001502911700002102926700002002947700001802967700001902985700002103004700002503025700002603050700002103076700001903097700001903116700002803135700002203163700002203185700001903207700002003226700001803246700001703264700001503281700002003296700002803316700001703344700001703361700002703378700002503405700002003430700002003450700002003470700002403490700001203514700001603526700002003542700002803562700001603590700002103606700001903627700002103646700002703667700002103694700002403715700001603739700002203755700002403777700002503801700001703826700001403843700002103857700002003878700002203898700001903920700002003939700001503959700002003974700002203994700002404016700002004040700001804060700002004078700002704098700001804125700001704143700002104160700001604181700001804197700002404215700002004239700002004259700002604279700001904305700002004324700002304344700002304367700002504390700002004415700003004435700001804465700002304483700001804506700002104524700001904545700002004564700001804584700001904602700002304621700002204644700002004666700001904686700002204705700002004727700001904747700002304766700002104789700002004810700002304830700002504853700002904878700002904907700001904936700002604955700001904981700002205000700002005022700002405042700002005066700001705086700001805103700002105121700001305142700003205155700002305187700002205210700002205232700002505254700002405279700002305303710003105326710006505357856003605422 2023 eng d00aWhole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.0 aWhole genome analysis of plasma fibrinogen reveals populationdif c2023 Jun 123 aUNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.
KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.
1 aHuffman, Jennifer, E1 aNicolas, Jayna1 aHahn, Julie1 aHeath, Adam, S1 aRaffield, Laura, M1 aYanek, Lisa, R1 aBrody, Jennifer, A1 aThibord, Florian1 aAlmasy, Laura1 aBartz, Traci, M1 aBielak, Lawrence, F1 aBowler, Russell, P1 aCarrasquilla, Germán, D1 aChasman, Daniel, I1 aChen, Ming-Huei1 aEmmert, David, B1 aGhanbari, Mohsen1 aHaessle, Jeffery1 aHottenga, Jouke-Jan1 aKleber, Marcus, E1 aLe, Ngoc-Quynh1 aLee, Jiwon1 aLewis, Joshua, P1 aLi-Gao, Ruifang1 aLuan, Jian'an1 aMalmberg, Anni1 aMangino, Massimo1 aMarioni, Riccardo, E1 aMartinez-Perez, Angel1 aPankratz, Nathan1 aPolasek, Ozren1 aRichmond, Anne1 aRodriguez, Benjamin, At1 aRotter, Jerome, I1 aSteri, Maristella1 aSuchon, Pierre1 aTrompet, Stella1 aWeiss, Stefan1 aZare, Marjan1 aAuer, Paul1 aCho, Michael, H1 aChristofidou, Paraskevi1 aDavies, Gail1 ade Geus, Eco1 aDeleuze, Jean-Francois1 aDelgado, Graciela, E1 aEkunwe, Lynette1 aFaraday, Nauder1 aGögele, Martin1 aGreinacher, Andreas1 aHe, Gao1 aHoward, Tom1 aJoshi, Peter, K1 aKilpeläinen, Tuomas, O1 aLahti, Jari1 aLinneberg, Allan1 aNaitza, Silvia1 aNoordam, Raymond1 aPaüls-Vergés, Ferran1 aRich, Stephen, S1 aRosendaal, Frits, R1 aRudan, Igor1 aRyan, Kathleen, A1 aSouto, Juan, Carlos1 avan Rooij, Frank, Ja1 aWang, Heming1 aZhao, Wei1 aBecker, Lewis, C1 aBeswick, Andrew1 aBrown, Michael, R1 aCade, Brian, E1 aCampbell, Harry1 aCho, Kelly1 aCrapo, James, D1 aCurran, Joanne, E1 ade Maat, Moniek, Pm1 aDoyle, Margaret1 aElliott, Paul1 aFloyd, James, S1 aFuchsberger, Christian1 aGrarup, Niels1 aGuo, Xiuqing1 aHarris, Sarah, E1 aHou, Lifang1 aKolcic, Ivana1 aKooperberg, Charles1 aMenni, Cristina1 aNauck, Matthias1 aO'Connell, Jeffrey, R1 aOrrù, Valeria1 aPsaty, Bruce, M1 aRäikkönen, Katri1 aSmith, Jennifer, A1 aSoria, José, Manuel1 aStott, David, J1 aVlieg, Astrid, van Hylcka1 aWatkins, Hugh1 aWillemsen, Gonneke1 aWilson, Peter1 aBen-Shlomo, Yoav1 aBlangero, John1 aBoomsma, Dorret1 aCox, Simon, R1 aDehghan, Abbas1 aEriksson, Johan, G1 aFiorillo, Edoardo1 aFornage, Myriam1 aHansen, Torben1 aHayward, Caroline1 aIkram, Arfan, M1 aJukema, Wouter1 aKardia, Sharon, Lr1 aLange, Leslie, A1 aMärz, Winfried1 aMathias, Rasika, A1 aMitchell, Braxton, D1 aMook-Kanamori, Dennis, O1 aMorange, Pierre-Emmanuel1 aPedersen, Oluf1 aPramstaller, Peter, P1 aRedline, Susan1 aReiner, Alexander1 aRidker, Paul, M1 aSilverman, Edwin, K1 aSpector, Tim, D1 aVölker, Uwe1 aWareham, Nick1 aWilson, James, F1 aYao, Jie1 aTrégouët, David-Alexandre1 aJohnson, Andrew, D1 aWolberg, Alisa, S1 ade Vries, Paul, S1 aSabater-Lleal, Maria1 aMorrison, Alanna, C1 aSmith, Nicholas, L1 aVA Million Veteran Program1 aNHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium uhttps://chs-nhlbi.org/node/9449