Title | Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study. |
Publication Type | Publication |
Year | 2022 |
Authors | Downie CG, Dimos SF, Bien SA, Hu Y, Darst BF, Polfus LM, Wang Y, Wojcik GL, Tao R, Raffield LM, Armstrong ND, Polikowsky HG, Below JE, Correa A, Irvin MR, Rasmussen-Torvik LJF, Carlson CS, Phillips LS, Liu S, Pankow JS, Rich SS, Rotter JI, Buyske S, Matise TC, North KE, Avery CL, Haiman CA, Loos RJF, Kooperberg C, Graff M, Highland HM |
Journal | Diabetologia |
Volume | 65 |
Issue | 3 |
Pagination | 477-489 |
Date Published | 2022 Mar |
ISSN | 1432-0428 |
Keywords | Blood Glucose, Diabetes Mellitus, Type 2, genome-wide association study, Genomics, Humans, Polymorphism, Single Nucleotide |
Abstract | AIMS/HYPOTHESIS: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits. However, most of these findings were based only on populations of European ancestry. To address this research gap, we examined the genetic basis of fasting glucose, fasting insulin and HbA in participants of the diverse Population Architecture using Genomics and Epidemiology (PAGE) Study.METHODS: We conducted a GWAS of fasting glucose (n = 52,267), fasting insulin (n = 48,395) and HbA (n = 23,357) in participants without diabetes from the diverse PAGE Study (23% self-reported African American, 46% Hispanic/Latino, 40% European, 4% Asian, 3% Native Hawaiian, 0.8% Native American), performing transethnic and population-specific GWAS meta-analyses, followed by fine-mapping to identify and characterise novel loci and independent secondary signals in known loci.RESULTS: Four novel associations were identified (p < 5 × 10), including three loci associated with fasting insulin, and a novel, low-frequency African American-specific locus associated with fasting glucose. Additionally, seven secondary signals were identified, including novel independent secondary signals for fasting glucose at the known GCK locus and for fasting insulin at the known PPP1R3B locus in transethnic meta-analysis.CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic architecture of glycaemic traits and highlight the continued importance of conducting genetic studies in diverse populations.DATA AVAILABILITY: Full summary statistics from each of the population-specific and transethnic results are available at NHGRI-EBI GWAS catalog ( https://www.ebi.ac.uk/gwas/downloads/summary-statistics ). |
DOI | 10.1007/s00125-021-05635-9 |
Alternate Journal | Diabetologia |
PubMed ID | 34951656 |
PubMed Central ID | PMC8810722 |
Grant List | N01HC95160 / HL / NHLBI NIH HHS / United States 75N98021D00004 / NH / NIH HHS / United States 75N90021D00004 / CL / CLC NIH HHS / United States 75N97021D00003 / LM / NLM NIH HHS / United States 75N92020D00002 / HL / NHLBI NIH HHS / United States HHSN268201300005C / HL / NHLBI NIH HHS / United States 75N95020D00004 / DA / NIDA NIH HHS / United States 75N92021D00002 / HL / NHLBI NIH HHS / United States HHSN268201500003C / HL / NHLBI NIH HHS / United States HHSN268201800012C / HL / NHLBI NIH HHS / United States U01 HG007419 / HG / NHGRI NIH HHS / United States HHSN268201300004C / HL / NHLBI NIH HHS / United States 75N95020D00007 / DA / NIDA NIH HHS / United States 75N92020D00005 / HL / NHLBI NIH HHS / United States 75N92021D00005 / WH / WHI NIH HHS / United States HHSN268201300001C / HL / NHLBI NIH HHS / United States 75N95021D00001 / DA / NIDA NIH HHS / United States UL1 RR025005 / RR / NCRR NIH HHS / United States HHSN268201800004I / HL / NHLBI NIH HHS / United States 75N98021D00002 / NH / NIH HHS / United States N01HC95163 / HL / NHLBI NIH HHS / United States U01 HG004790 / HG / NHGRI NIH HHS / United States UL1 TR001079 / TR / NCATS NIH HHS / United States R01 HD030880 / HD / NICHD NIH HHS / United States 75N94020D00003 / HD / NICHD NIH HHS / United States R03 AI133172 / AI / NIAID NIH HHS / United States HHSN268201800014I / HB / NHLBI NIH HHS / United States U01 HG004802 / HG / NHGRI NIH HHS / United States U01 HG007416 / HG / NHGRI NIH HHS / United States P20 MD000170 / MD / NIMHD NIH HHS / United States R01 HL059367 / HL / NHLBI NIH HHS / United States S10 OD028685 / OD / NIH HHS / United States 75N92020D00001 / HL / NHLBI NIH HHS / United States N01HC95169 / HL / NHLBI NIH HHS / United States R01 HL123782 / HL / NHLBI NIH HHS / United States 75N94021D00001 / HD / NICHD NIH HHS / United States R01 HL086694 / HL / NHLBI NIH HHS / United States R01 HL142302 / HL / NHLBI NIH HHS / United States N02 HL64278 / HL / NHLBI NIH HHS / United States R01 DK110113 / DK / NIDDK NIH HHS / United States N01HC65236 / HL / NHLBI NIH HHS / United States R01 DK104371 / DK / NIDDK NIH HHS / United States 75N99021D00001 / OF / ORFDO NIH HHS / United States U01 DK098246 / DK / NIDDK NIH HHS / United States N01HC65235 / HL / NHLBI NIH HHS / United States R01 AG065357 / AG / NIA NIH HHS / United States U01 HG004402 / HG / NHGRI NIH HHS / United States 75N95020D00003 / DA / NIDA NIH HHS / United States N01HC95164 / HL / NHLBI NIH HHS / United States N02HL64278 / HL / NHLBI NIH HHS / United States HHSN268201800014C / HL / NHLBI NIH HHS / United States 75N99020D00005 / OF / ORFDO NIH HHS / United States 75N92022D00007 / HL / NHLBI NIH HHS / United States N01HC95162 / HL / NHLBI NIH HHS / United States R01 HL093029 / HL / NHLBI NIH HHS / United States R01 HL136666 / HL / NHLBI NIH HHS / United States N01HC65234 / HL / NHLBI NIH HHS / United States 75N92020D00003 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States N01HC95168 / HL / NHLBI NIH HHS / United States HHSN268201200008C / HL / NHLBI NIH HHS / United States 75N92021D00001 / HL / NHLBI NIH HHS / United States T32 HL129982 / HL / NHLBI NIH HHS / United States R01 HL108427 / HL / NHLBI NIH HHS / United States U01 HG004729 / HG / NHGRI NIH HHS / United States HHSN268201800003I / HL / NHLBI NIH HHS / United States 75N93020D00002 / AI / NIAID NIH HHS / United States 75N90021D00002 / CL / CLC NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States HHSN268201700002C / HL / NHLBI NIH HHS / United States N01HC65233 / HL / NHLBI NIH HHS / United States HHSN268201800007I / HL / NHLBI NIH HHS / United States HHSN268201700001I / HL / NHLBI NIH HHS / United States HHSN268201800013I / MD / NIMHD NIH HHS / United States 75N96020D00002 / ES / NIEHS NIH HHS / United States R01 HL151152 / HL / NHLBI NIH HHS / United States N01HC65237 / HL / NHLBI NIH HHS / United States U01 HG004803 / HG / NHGRI NIH HHS / United States 75N99020D00003 / OF / ORFDO NIH HHS / United States 75N99021D00002 / OF / ORFDO NIH HHS / United States HHSN268201700004I / HL / NHLBI NIH HHS / United States 75N95020D00002 / DA / NIDA NIH HHS / United States N01HC95165 / HL / NHLBI NIH HHS / United States 75N98021D00005 / NH / NIH HHS / United States U01 NS041588 / NS / NINDS NIH HHS / United States N01HC95159 / HL / NHLBI NIH HHS / United States P01 CA033619 / CA / NCI NIH HHS / United States R56 HG010297 / HG / NHGRI NIH HHS / United States HHSN268201800012I / HL / NHLBI NIH HHS / United States 75N92021D00003 / WH / WHI NIH HHS / United States 75N99020D00007 / OF / ORFDO NIH HHS / United States 75N94020D00007 / HD / NICHD NIH HHS / United States UL1 TR001420 / TR / NCATS NIH HHS / United States D43 TW009077 / TW / FIC NIH HHS / United States 75N90020D00002 / CL / CLC NIH HHS / United States N01HC95161 / HL / NHLBI NIH HHS / United States P30 DK020541 / DK / NIDDK NIH HHS / United States I01 CX001737 / CX / CSRD VA / United States 75N92020D00004 / HL / NHLBI NIH HHS / United States 75N99020D00004 / OF / ORFDO NIH HHS / United States HHSN268201800011C / HL / NHLBI NIH HHS / United States 75N92020D00007 / HL / NHLBI NIH HHS / United States 75N99020D00006 / OF / ORFDO NIH HHS / United States R21 DK099716 / DK / NIDDK NIH HHS / United States R01 CA054281 / CA / NCI NIH HHS / United States UL1 TR002378 / TR / NCATS NIH HHS / United States HHSN268201300003C / HL / NHLBI NIH HHS / United States 75N94021D00002 / NR / NINR NIH HHS / United States HHSN268201500003I / HL / NHLBI NIH HHS / United States KL2 TR002490 / TR / NCATS NIH HHS / United States R01 HL142825 / HL / NHLBI NIH HHS / United States 75N92021D00006 / HL / NHLBI NIH HHS / United States R01 DK124097 / DK / NIDDK NIH HHS / United States HHSN268201700005C / HL / NHLBI NIH HHS / United States HHSN268201700001C / HL / NHLBI NIH HHS / United States 75N96020D00003 / ES / NIEHS NIH HHS / United States R35 HL155466 / HL / NHLBI NIH HHS / United States N01HC95167 / HL / NHLBI NIH HHS / United States HHSN268201700003C / HL / NHLBI NIH HHS / United States 75N98020D00007 / NH / NIH HHS / United States R18 DK066204 / DK / NIDDK NIH HHS / United States U01 CA098758 / CA / NCI NIH HHS / United States HHSN268201800015I / HB / NHLBI NIH HHS / United States HHSN268201700004C / HL / NHLBI NIH HHS / United States 75N95020D00005 / DA / NIDA NIH HHS / United States UL1 TR000040 / TR / NCATS NIH HHS / United States 75N99020D00002 / OF / ORFDO NIH HHS / United States HHSN268201700002I / HL / NHLBI NIH HHS / United States 75N90020D00003 / CL / CLC NIH HHS / United States I01 BX005831 / BX / BLRD VA / United States HHSN268201800010I / HB / NHLBI NIH HHS / United States HHSN268201700005I / HL / NHLBI 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 UL1 TR001881 / TR / NCATS NIH HHS / United States HHSN268201800011I / HB / NHLBI NIH HHS / United States HHSN268201800005I / HL / NHLBI NIH HHS / United States T32 HL007055 / HL / NHLBI NIH HHS / United States U01 CA136792 / CA / NCI NIH HHS / United States U34 DK091958 / DK / NIDDK NIH HHS / United States HHSN268201700003I / HL / NHLBI NIH HHS / United States R01 HG010297 / HG / NHGRI NIH HHS / United States HHSN268201200008I / HL / NHLBI NIH HHS / United States HHSN268201800006I / HL / NHLBI NIH HHS / United States R21 AI156161 / AI / NIAID NIH HHS / United States R37 CA054281 / CA / NCI NIH HHS / United States 75N91021D00001 / CA / NCI NIH HHS / United States 75N92021D00004 / WH / WHI NIH HHS / United States UL1 TR003098 / TR / NCATS NIH HHS / United States UL1 TR000371 / TR / NCATS NIH HHS / United States |
Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study.
MS#:
0555
ECI:
Yes
Manuscript Affiliation:
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
Manuscript Status:
Published