Ultraconserved Elements in the Human Genome: Association and Transmission Analyses of Highly Constrained Single-Nucleotide Polymorphisms

被引:13
作者
Chiang, Charleston W. K. [1 ,2 ,3 ,4 ,5 ]
Liu, Ching-Ti [6 ]
Lettre, Guillaume [7 ,8 ]
Lange, Leslie A. [9 ]
Jorgensen, Neal W. [10 ]
Keating, Brendan J. [11 ,12 ]
Vedantam, Sailaja [1 ,2 ,3 ,5 ]
Nock, Nora L. [13 ]
Franceschini, Nora [14 ]
Reiner, Alex P. [15 ]
Demerath, Ellen W. [16 ]
Boerwinkle, Eric [17 ]
Rotter, Jerome I. [18 ]
Wilson, James G. [19 ]
North, Kari E. [14 ]
Papanicolaou, George J. [20 ]
Cupples, L. Adrienne [6 ,20 ]
Murabito, Joanne M. [21 ,22 ]
Hirschhorn, Joel N. [1 ,2 ,3 ,4 ,5 ]
机构
[1] Childrens Hosp, Genet Program, Boston, MA 02115 USA
[2] Childrens Hosp, Div Genet, Boston, MA 02115 USA
[3] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA
[5] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA
[6] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA
[7] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada
[8] Inst Cardiol Montreal, Montreal, PQ H1T 1C8, Canada
[9] Univ N Carolina, Dept Genet, Chapel Hill, NC USA
[10] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA
[11] Univ Penn, Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA
[12] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
[13] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA
[14] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA
[15] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA
[16] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA
[17] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA
[18] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA
[19] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA
[20] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA
[21] Framingham Heart Dis Epidemiol Study, Framingham, MA USA
[22] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02215 USA
基金
美国国家科学基金会;
关键词
CONSERVED NONCODING SEQUENCES; WIDE ASSOCIATION; GENOTYPING ERRORS; LOCI; STRATIFICATION; MUTATION; DISEASES; TRAITS; DESIGN; SUBSET;
D O I
10.1534/genetics.112.141945
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:253 / U515
页数:28
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