Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts.

TitleType 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts.
Publication TypeJournal Article
Year of Publication2022
AuthorsDiCorpo, D, LeClair, J, Cole, JB, Sarnowski, C, Ahmadizar, F, Bielak, LF, Blokstra, A, Bottinger, EP, Chaker, L, Chen, Y-DI, Chen, Y, de Vries, PS, Faquih, T, Ghanbari, M, Gudmundsdottir, V, Guo, X, Hasbani, NR, Ibi, D, M Ikram, A, Kavousi, M, Leonard, HL, Leong, A, Mercader, JM, Morrison, AC, Nadkarni, GN, Nalls, MA, Noordam, R, Preuss, M, Smith, JA, Trompet, S, Vissink, P, Yao, J, Zhao, W, Boerwinkle, E, Goodarzi, MO, Gudnason, V, J Jukema, W, Kardia, SLR, Loos, RJF, Liu, C-T, Manning, AK, Mook-Kanamori, D, Pankow, JS, H Picavet, SJ, Sattar, N, Simonsick, EM, Verschuren, WMMonique, van Dijk, KWillems, Florez, JC, Rotter, JI, Meigs, JB, Dupuis, J, Udler, MS
JournalDiabetes Care
Volume45
Issue3
Pagination674-683
Date Published2022 03 01
ISSN1935-5548
KeywordsAlleles, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Genetic Loci, Humans, Obesity, Pharmaceutical Preparations
Abstract

OBJECTIVE: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed.

RESEARCH DESIGN AND METHODS: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD).

RESULTS: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway.

CONCLUSIONS: Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.

DOI10.2337/dc21-1395
Alternate JournalDiabetes Care
PubMed ID35085396
PubMed Central IDPMC8918228
Grant List75N92020D00005 / HL / NHLBI NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
R01 DK127139 / DK / NIDDK NIH HHS / United States
R01 DK107786 / DK / NIDDK NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
HHSN268201500003I / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
R56 DK126930 / DK / NIDDK NIH HHS / United States
R01 DK078616 / DK / NIDDK NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
75N92020D00002 / HL / NHLBI NIH HHS / United States
HHSN268201500003C / HL / NHLBI NIH HHS / United States
R03 DK118305 / DK / NIDDK NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01HC95163 / HL / NHLBI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
R01 HL087660 / HL / NHLBI NIH HHS / United States
T32 GM074905 / GM / NIGMS NIH HHS / United States
K23 DK114551 / DK / NIDDK NIH HHS / United States
U10 HL054464 / HL / NHLBI NIH HHS / United States
75N92020D00001 / HL / NHLBI NIH HHS / United States
N01HC95169 / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 HL142302 / HL / NHLBI NIH HHS / United States
K99 DK127196 / DK / NIDDK NIH HHS / United States
R01 DK110113 / DK / NIDDK NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC95164 / HL / NHLBI NIH HHS / United States
N02HL64278 / HL / NHLBI NIH HHS / United States
R01 NR012459 / NR / NINR NIH HHS / United States
75N92020D00003 / HL / NHLBI NIH HHS / United States
N01HC95162 / HL / NHLBI NIH HHS / United States
U01 HL054464 / HL / NHLBI NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
N01HC95168 / HL / NHLBI NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
U10 HL054457 / HL / NHLBI NIH HHS / United States
U10 HL054481 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
HHSN268201700002C / HL / NHLBI NIH HHS / United States
U01 HL054457 / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
N01HC95165 / HL / NHLBI NIH HHS / United States
N01HC95159 / HL / NHLBI NIH HHS / United States
R56 HG010297 / HG / NHGRI NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
U01 HG011723 / HG / NHGRI NIH HHS / United States
N01HC95161 / HL / NHLBI NIH HHS / United States
UL1 TR001420 / TR / NCATS NIH HHS / United States
75N92020D00004 / HL / NHLBI NIH HHS / United States
75N92020D00007 / HL / NHLBI NIH HHS / United States
U01 DK078616 / DK / NIDDK NIH HHS / United States
R01 AG028050 / AG / NIA NIH HHS / United States
HHSN268201700005C / HL / NHLBI NIH HHS / United States
HHSN268201700001C / HL / NHLBI NIH HHS / United States
N01HC95167 / HL / NHLBI NIH HHS / United States
HHSN268201700003C / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
U01 HL054481 / HL / NHLBI NIH HHS / United States
HHSN268201700004C / HL / NHLBI NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
R01 HL151855 / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
UM1 DK078616 / DK / NIDDK NIH HHS / United States
75N92020D00006 / HL / NHLBI NIH HHS / United States
N01HC95166 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
HHSN271201200022C / DA / NIDA NIH HHS / United States
K23 DK107908 / DK / NIDDK NIH HHS / United States