Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

被引：37

作者：

Taub, Margaret A. ^{[1
]}

Conomos, Matthew P. ^{[2
]}

Keener, Rebecca ^{[3
]}

Iyer, Kruthika R. ^{[4
]}

Weinstock, Joshua S. ^{[5
,6
]}

Yanek, Lisa R. ^{[7
]}

Lane, John ^{[8
]}

Miller-Fleming, Tyne W. ^{[9
]}

Brody, Jennifer A. ^{[10
]}

Raffield, Laura M. ^{[11
]}

McHugh, Caitlin P. ^{[2
]}

Jain, Deepti ^{[2
]}

Gogarten, Stephanie M. ^{[2
]}

Laurie, Cecelia A. ^{[2
]}

Keramati, Ali ^{[12
]}

Arvanitis, Marios ^{[13
]}

Smith, Albert, V ^{[5
,6
]}

Heavner, Benjamin ^{[2
]}

Barwick, Lucas ^{[14
]}

Becker, Lewis C. ^{[7
]}

Bis, Joshua C. ^{[10
]}

Blangero, John ^{[15
,16
]}

Bleecker, Eugene R. ^{[17
,18
]}

Burchard, Esteban G. ^{[19
,20
]}

Celedon, Juan C. ^{[21
]}

Chang, Yen Pei C. ^{[22
]}

Custer, Brian ^{[23
,24
]}

Darbar, Dawood ^{[25
]}

de las Fuentes, Lisa ^{[26
]}

DeMeo, Dawn L. ^{[27
,28
]}

Freedman, Barry, I ^{[29
]}

Garrett, Melanie E. ^{[30
,31
,32
]}

Gladwin, Mark T. ^{[33
]}

Heckbert, Susan R. ^{[34
,35
,36
]}

Hidalgo, Bertha A. ^{[37
]}

Irvin, Marguerite R. ^{[37
]}

Islam, Talat ^{[38
]}

Johnson, W. Craig ^{[39
]}

Kaab, Stefan ^{[40
,41
]}

Launer, Lenore ^{[42
]}

Lee, Jiwon ^{[43
]}

Liu, Simin ^{[44
,45
]}

Moscati, Arden ^{[46
]}

North, Kari E. ^{[47
]}

Peyser, Patricia A. ^{[48
]}

Rafaels, Nicholas ^{[49
]}

Seidman, Christine ^{[50
]}

Weeks, Daniel E. ^{[51
,52
]}

Wen, Fayun ^{[53
,54
]}

Wheeler, Marsha M. ^{[55
]}

机构：

[1] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

[2] Univ Washington, Dept Biostat, Sch Publ Hlth, Seattle, WA 98195 USA

[3] Johns Hopkins Whiting Sch Engn, Dept Biomed Engn, Baltimore, MD USA

[4] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[5] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[7] Johns Hopkins Sch Med, Dept Med, GeneSTAR Res Program, Baltimore, MD 21205 USA

[8] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[9] Vanderbilt Univ, Med Ctr, Dept Med, Div Genet Med, Nashville, TN USA

[10] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA USA

[11] Univ N Carolina, Dept Genet, Chapel Hill, NC USA

[12] Johns Hopkins Sch Med, Dept Cardiol, Baltimore, MD USA

[13] Johns Hopkins Sch Med, Dept Med, Div Cardiol, Baltimore, MD USA

[14] Emmes Co LLC, LTRC Data Coordinating Ctr, Rockville, MD USA

[15] Univ Texas Rio Grande Valley, Sch Med, Dept Human Genet, Brownsville, TX USA

[16] Univ Texas Rio Grande Valley, Sch Med, South Texas Diabet & Obes Inst, Brownsville, TX USA

[17] Univ Arizona, Dept Med, Div Genet Genom & Precis Med, Tucson, AZ USA

[18] Univ Arizona, Div Pharmacogen, Tucson, AZ USA

[19] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[20] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[21] Univ Pittsburgh, UPMC Childrens Hosp Pittsburgh, Div Pediat Pulm Med, Pittsburgh, PA USA

[22] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA

[23] Vitalant Res Inst, San Francisco, CA USA

[24] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA USA

[25] Univ Illinois, Div Cardiol, Chicago, IL USA

[26] Washington Univ, Sch Med St Louis, Dept Med, Cardiovasc Div, St Louis, MO USA

[27] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA

[28] Harvard Med Sch, Boston, MA 02115 USA

[29] Wake Forest Sch Med, Dept Internal Med, Sect Nephrol, Winston Salem, NC USA

[30] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[31] Duke Univ, Med Ctr, Duke Comprehens Sickle Cell Ctr, Durham, NC USA

[32] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC USA

[33] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA

[34] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[35] Univ Washington, Dept Epidemiol, Seattle, WA USA

[36] Kaiser Permanente Washington Hlth Res Inst, Seattle, WA USA

[37] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA

[38] Univ Southern Calif, Dept Populat & Publ Hlth Sci, Div Environm Hlth, Los Angeles, CA USA

[39] Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98195 USA

[40] Ludwig Maximilians Univ Munchen, Dept Med 1, Univ Hosp Munich, Munich, Germany

[41] German Ctr Cardiovasc Res DZHK, Partner Site Munich Heart Alliance, Munich, Germany

[42] NIA, Lab Epidemiol & Populat Sci, NIH, Bethesda, MD 20892 USA

[43] Brigham & Womens Hosp, Dept Med, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA

[44] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA

[45] Brown Univ, Brown Ctr Global Cardiometab Hlth, Providence, RI 02912 USA

[46] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[47] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[48] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA

[49] Univ Colorado Denver, Dept Med, Anschutz Med Campus, Aurora, CO USA

[50] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

来源：

CELL GENOMICS | 2022年 / 2卷 / 01期

基金：

美国国家卫生研究院;

关键词：

WIDE ASSOCIATION; CARDIOVASCULAR-DISEASE; VARIANTS; LOCI; METAANALYSIS; APOLLO; PATHOGENICITY; EXPRESSION; FRAMEWORK; BIOLOGY;

D O I：

10.1016/j.xgen.2021.100084

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWASs for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally diverse individuals (European, African, Asian, and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole-genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n = 109,122 individuals. We identified 59 sentinel variants (p < 5 x 10(-9)) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated that the independent signals colocalized with cell-type-specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated that our TL polygenic trait scores (PTSs) were associated with an increased risk of cancer-related phenotypes.

引用

页数：22

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