03691nas a2200649 4500008004100000022001400041245014200055210006900197260001300266300001100279490000800290520184900298653001202147653001202159653001602171653002002187653001002207653002302217653000902240653002502249653001102274653002002285653002202305653001802327653001302345653001102358653002502369653000902394653000902403653001302412653001402425653003602439653000902475653001702484653001602501100002802517700001802545700002202563700002102585700002302606700002402629700002202653700001802675700002302693700002002716700002302736700002102759700002202780700002102802700001902823700002802842700002502870700002402895700002402919710006202943856003603005 2012 eng d a1943-263100aUltraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms.0 aUltraconserved elements in the human genome association and tran c2012 Sep a253-660 v1923 a
Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.
10aAlleles10aAnimals10aBody Height10aBody Mass Index10aChild10aConserved Sequence10aDogs10aEvolution, Molecular10aFemale10aGenetic Fitness10aGenetic Variation10aGenome, Human10aGenotype10aHumans10aInheritance Patterns10aMale10aMice10aPedigree10aPhenotype10aPolymorphism, Single Nucleotide10aRats10aReproduction10aYoung Adult1 aChiang, Charleston, W K1 aLiu, Ching-Ti1 aLettre, Guillaume1 aLange, Leslie, A1 aJorgensen, Neal, W1 aKeating, Brendan, J1 aVedantam, Sailaja1 aNock, Nora, L1 aFranceschini, Nora1 aReiner, Alex, P1 aDemerath, Ellen, W1 aBoerwinkle, Eric1 aRotter, Jerome, I1 aWilson, James, G1 aNorth, Kari, E1 aPapanicolaou, George, J1 aCupples, Adrienne, L1 aMurabito, Joanne, M1 aHirschhorn, Joel, N1 aGenetic Investigation of ANthropometric Traits Consortium uhttps://chs-nhlbi.org/node/154403769nas a2200937 4500008004100000022001400041245009400055210006900149260001600218300001200234490000700246520111800253653002201371653001601393653002301409653004001432653001101472653001701483653002201500653003401522653001101556653001401567653001801581100002501599700001801624700001801642700002501660700002101685700001801706700002301724700002301747700002201770700001201792700002001804700002301824700002201847700002201869700002001891700002801911700002201939700002201961700002001983700002302003700001802026700002802044700001802072700002202090700002202112700001902134700002002153700001702173700002302190700002302213700002202236700002102258700001802279700002202297700002202319700002202341700002002363700002202383700001402405700001502419700002202434700002202456700002402478700002402502700002402526700001702550700002202567700001702589700002102606700002402627700002302651700002502674700002302699700002402722700002402746700002502770856003602795 2014 eng d a1460-208300aMeta-analysis of loci associated with age at natural menopause in African-American women.0 aMetaanalysis of loci associated with age at natural menopause in c2014 Jun 15 a3327-420 v233 aAge at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA.
10aAfrican Americans10aAge Factors10aChromosomes, Human10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenetic Variation10aGenome-Wide Association Study10aHumans10aMenopause10aUnited States1 aChen, Christina, T L1 aLiu, Ching-Ti1 aChen, Gary, K1 aAndrews, Jeanette, S1 aArnold, Alice, M1 aDreyfus, Jill1 aFranceschini, Nora1 aGarcia, Melissa, E1 aKerr, Kathleen, F1 aLi, Guo1 aLohman, Kurt, K1 aMusani, Solomon, K1 aNalls, Michael, A1 aRaffel, Leslie, J1 aSmith, Jennifer1 aAmbrosone, Christine, B1 aBandera, Elisa, V1 aBernstein, Leslie1 aBritton, Angela1 aBrzyski, Robert, G1 aCappola, Anne1 aCarlson, Christopher, S1 aCouper, David1 aDeming, Sandra, L1 aGoodarzi, Mark, O1 aHeiss, Gerardo1 aJohn, Esther, M1 aLu, Xiaoning1 aLe Marchand, Loïc1 aMarciante, Kristin1 aMcKnight, Barbara1 aMillikan, Robert1 aNock, Nora, L1 aOlshan, Andrew, F1 aPress, Michael, F1 aVaiyda, Dhananjay1 aWoods, Nancy, F1 aTaylor, Herman, A1 aZhao, Wei1 aZheng, Wei1 aEvans, Michele, K1 aHarris, Tamara, B1 aHenderson, Brian, E1 aKardia, Sharon, L R1 aKooperberg, Charles1 aLiu, Yongmei1 aMosley, Thomas, H1 aPsaty, Bruce1 aWellons, Melissa1 aWindham, Beverly, G1 aZonderman, Alan, B1 aCupples, Adrienne, L1 aDemerath, Ellen, W1 aHaiman, Christopher1 aMurabito, Joanne, M1 aRajkovic, Aleksandar uhttps://chs-nhlbi.org/node/6552