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Identification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.

TitleIdentification of novel and rare variants associated with handgrip strength using whole genome sequence data from the NHLBI Trans-Omics in Precision Medicine (TOPMed) Program.
Publication TypeJournal Article
Year of Publication2021
AuthorsSarnowski C, Chen H, Biggs ML, Wassertheil-Smoller S, Bressler J, Irvin MR, Ryan KA, Karasik D, Arnett DK, L Cupples A, Fardo DW, Gogarten SM, Heavner BD, Jain D, Kang HMin, Kooperberg C, Mainous AG, Mitchell BD, Morrison AC, O'Connell JR, Psaty BM, Rice K, Smith AV, Vasan RS, B Windham G, Kiel DP, Murabito JM, Lunetta KL
Corporate AuthorsTOPMed Longevity and Healthy Aging Working Group, from the NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium
JournalPLoS One
Volume16
Issue7
Paginatione0253611
Date Published2021
ISSN1932-6203
Abstract

Handgrip strength is a widely used measure of muscle strength and a predictor of a range of morbidities including cardiovascular diseases and all-cause mortality. Previous genome-wide association studies of handgrip strength have focused on common variants primarily in persons of European descent. We aimed to identify rare and ancestry-specific genetic variants associated with handgrip strength by conducting whole-genome sequence association analyses using 13,552 participants from six studies representing diverse population groups from the Trans-Omics in Precision Medicine (TOPMed) Program. By leveraging multiple handgrip strength measures performed in study participants over time, we increased our effective sample size by 7-12%. Single-variant analyses identified ten handgrip strength loci among African-Americans: four rare variants, five low-frequency variants, and one common variant. One significant and four suggestive genes were identified associated with handgrip strength when aggregating rare and functional variants; all associations were ancestry-specific. We additionally leveraged the different ancestries available in the UK Biobank to further explore the ancestry-specific association signals from the single-variant association analyses. In conclusion, our study identified 11 new loci associated with handgrip strength with rare and/or ancestry-specific genetic variations, highlighting the added value of whole-genome sequencing in diverse samples. Several of the associations identified using single-variant or aggregate analyses lie in genes with a function relevant to the brain or muscle or were reported to be associated with muscle or age-related traits. Further studies in samples with sequence data and diverse ancestries are needed to confirm these findings.

DOI10.1371/journal.pone.0253611
Alternate JournalPLoS One
PubMed ID34214102
PubMed Central IDPMC8253404
Grant ListU01 HL054472 / HL / NHLBI NIH HHS / United States
N01 HC085086 / HC / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
N01 HC085082 / HC / NHLBI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U24 AG051129 / AG / NIA NIH HHS / United States
HHSN268201700004C / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 HL121007 / HL / NHLBI NIH HHS / United States
R01 HL131136 / HL / NHLBI NIH HHS / United States
N01 HC085081 / HC / NHLBI NIH HHS / United States
HHSN268201600002C / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
HHSN268201600018C / HL / NHLBI NIH HHS / United States
R01 HL092577 / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
N01 HC085083 / HC / NHLBI NIH HHS / United States
U01 HL054509 / HL / NHLBI NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U01 HL137181 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
N01 HC085080 / HC / NHLBI NIH HHS / United States
HHSN268201700002C / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
HHSN268201500015C / HL / NHLBI NIH HHS / United States
HHSN268201600003C / HL / NHLBI NIH HHS / United States
HHSN268201600033C / ES / NIEHS NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
HHSN268201600004C / HL / NHLBI NIH HHS / United States
U01 HL072515 / HL / NHLBI NIH HHS / United States
HHSN268201500014C / HL / NHLBI NIH HHS / United States
HHSN268201600001C / HL / NHLBI NIH HHS / United States
HHSN268201700005C / HL / NHLBI NIH HHS / United States
HHSN268201700001C / HL / NHLBI NIH HHS / United States
N01HC85082 / HL / NHLBI NIH HHS / United States
HHSN268201700003C / HL / NHLBI NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
UM1 HG008898 / HG / NHGRI NIH HHS / United States
R01 HL117626 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01 HC085079 / HC / NHLBI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
U01 HL054495 / HL / NHLBI NIH HHS / United States
R01 AG018728 / AG / NIA NIH HHS / United States
R01 HL055673 / HL / NHLBI NIH HHS / United States
U01 HL054473 / HL / NHLBI NIH HHS / United States