A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
14
09
2021
accepted:
05
04
2022
entrez:
2
6
2022
pubmed:
3
6
2022
medline:
7
6
2022
Statut:
epublish
Résumé
Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank. Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders. We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
Sections du résumé
BACKGROUND
Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.
METHODS AND FINDINGS
Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.
CONCLUSIONS
We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
Identifiants
pubmed: 35653334
doi: 10.1371/journal.pgen.1010193
pii: PGENETICS-D-21-01241
pmc: PMC9162317
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010193Subventions
Organisme : NHGRI NIH HHS
ID : R01 HG009974
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142302
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101855
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK101478
Pays : United States
Organisme : BLRD VA
ID : I01 BX004821
Pays : United States
Organisme : CSRD VA
ID : IK2 CX001907
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG010297
Pays : United States
Déclaration de conflit d'intérêts
I have read the journal’s policy and the authors of this manuscript have the following competing interests: CJO is a full-time employee of Novartis Institutes of Biomedical Research. The remaining authors have declared that no competing interests exist.
Références
Econ Hum Biol. 2009 Jul;7(2):137-52
pubmed: 19628438
J Vasc Res. 2001 Jan-Feb;38(1):20-9
pubmed: 11173991
Circulation. 2018 Dec 18;138(25):2869-2880
pubmed: 30566020
Bioinformatics. 2014 Aug 15;30(16):2375-6
pubmed: 24733291
Am J Hum Genet. 2018 Nov 1;103(5):691-706
pubmed: 30388399
Ann Epidemiol. 2014 Mar;24(3):174-179.e2
pubmed: 24360853
Nat Commun. 2017 Nov 28;8(1):1826
pubmed: 29184056
Am J Hum Genet. 2019 Oct 3;105(4):763-772
pubmed: 31564439
Muscle Nerve. 2001 Sep;24(9):1134-41
pubmed: 11494265
BMJ. 2016 Mar 08;352:i582
pubmed: 26956984
Nat Genet. 2018 Nov;50(11):1514-1523
pubmed: 30275531
Cell. 2019 Oct 17;179(3):589-603
pubmed: 31607513
Nat Genet. 2014 Nov;46(11):1173-86
pubmed: 25282103
Am J Epidemiol. 2010 May 15;171(10):1109-15
pubmed: 20418276
Nature. 2017 Feb 9;542(7640):186-190
pubmed: 28146470
Circ Arrhythm Electrophysiol. 2017 Jan;10(1):
pubmed: 28039282
PLoS Genet. 2013 Jun;9(6):e1003566
pubmed: 23785302
Nat Genet. 2016 Sep;48(9):1031-6
pubmed: 27479909
PLoS Genet. 2019 Apr 18;15(4):e1008110
pubmed: 30998689
Hum Mol Genet. 2018 Oct 15;27(20):3641-3649
pubmed: 30124842
Int J Epidemiol. 2012 Oct;41(5):1419-33
pubmed: 22825588
Nat Genet. 2015 Mar;47(3):291-5
pubmed: 25642630
Nat Genet. 2015 Nov;47(11):1236-41
pubmed: 26414676
Int J Epidemiol. 1991 Dec;20(4):1001-9
pubmed: 1800396
Soc Hist Med. 1994 Aug;7(2):297-320
pubmed: 11639331
Sci Rep. 2015 Nov 16;5:16645
pubmed: 26568383
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
PLoS Med. 2020 Oct 8;17(10):e1003288
pubmed: 33031386
PLoS Genet. 2019 Feb 1;15(2):e1007951
pubmed: 30707692
Am J Hum Genet. 2019 Jan 3;104(1):65-75
pubmed: 30595370
Stat Methods Med Res. 2017 Oct;26(5):2333-2355
pubmed: 26282889
Oncotarget. 2017 Jan 31;8(5):7891-7899
pubmed: 27903959
BMC Med. 2018 Oct 25;16(1):187
pubmed: 30355295
Am J Hum Genet. 2017 Apr 6;100(4):635-649
pubmed: 28366442
Diabetes. 2020 May;69(5):1000-1010
pubmed: 32051148
Am J Epidemiol. 2014 Jul 15;180(2):215-22
pubmed: 24944287
Am J Hum Genet. 2021 Apr 1;108(4):564-582
pubmed: 33713608
JMIR Med Inform. 2019 Nov 29;7(4):e14325
pubmed: 31553307
Eur Heart J. 2012 Nov;33(21):2709-17
pubmed: 22977225
Bioinformatics. 2010 Sep 1;26(17):2190-1
pubmed: 20616382
Endocrinol Diabetes Metab. 2020 Aug 17;4(1):e00175
pubmed: 33532615
Nature. 2019 Jun;570(7762):514-518
pubmed: 31217584
Nat Genet. 2018 Nov;50(11):1505-1513
pubmed: 30297969
Diabetes Care. 2021 Mar;44(3):722-730
pubmed: 33441420
Nat Genet. 2020 Jul;52(7):680-691
pubmed: 32541925
Rand Health Q. 2016 May 9;5(4):13
pubmed: 28083423
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
N Engl J Med. 2015 Apr 23;372(17):1608-18
pubmed: 25853659
PLoS One. 2017 Jul 7;12(7):e0175508
pubmed: 28686612
Commun Biol. 2019 Mar 27;2:119
pubmed: 30937401
Prev Chronic Dis. 2017 Dec 14;14:E135
pubmed: 29240552
Nat Genet. 2006 Aug;38(8):904-9
pubmed: 16862161
Nat Commun. 2019 Sep 27;10(1):4393
pubmed: 31562340
Am J Hum Genet. 2020 Apr 2;106(4):535-548
pubmed: 32243820
J Clin Epidemiol. 2016 Feb;70:214-23
pubmed: 26441289
Int J Epidemiol. 2018 Dec 1;47(6):2059-2069
pubmed: 30137430
Nutr Rev. 2016 Mar;74(3):149-65
pubmed: 26928678