A novel splice-affecting HNF1A variant with large population impact on diabetes in Greenland

The genetic disease architecture of Inuit includes a large number of common high-impact variants. Identification of such variants contributes to our understanding of the genetic aetiology of diseases and improves global equity in genomic personalised medicine. We aimed to identify and characterise novel variants in genes associated with Maturity Onset Diabetes of the Young (MODY) in the Greenlandic population. Using combined data from Greenlandic population cohorts of 4497 individuals, including 448 whole genome sequenced individuals, we screened 14 known MODY genes for previously identified and novel variants. We functionally characterised an identified novel variant and assessed its association with diabetes prevalence and cardiometabolic traits and population impact. We identified a novel variant in the known MODY gene HNF1A with an allele frequency of 1.9% in the Greenlandic Inuit and absent elsewhere. Functional assays indicate that it prevents normal splicing of the gene. The variant caused lower 30-min insulin (β = −232 pmol/L, βSD = −0.695, P = 4.43 × 10−4) and higher 30-min glucose (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) during an oral glucose tolerance test. Furthermore, the variant was associated with type 2 diabetes (OR 4.35, P = 7.24 × 10−6) and HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10−3). The variant explained 2.5% of diabetes variance in Greenland. The reported variant has the largest population impact of any previously reported variant within a MODY gene. Together with the recessive TBC1D4 variant, we show that close to 1 in 5 cases of diabetes (18%) in Greenland are associated with high-impact genetic variants compared to 1–3% in large populations. Novo Nordisk Foundation, Independent Research Fund Denmark, and Karen Elise Jensen's Foundation. HNF1A-mi pinngoqqaammi allannguut suussusersineqarlaaq, pinngoqqaatinik allannguinermut sunniuteqartoq, Kalaallit Nunaanni diabetesimik nappaateqarnermut annertuumik sunniutilik. Naggueqatigiit Inuit akornanni nappaatit pinngoqqaatikkut katitigaanerat, pinngoqqaatikkut allannguutaagajuttunik amerlaqisunik nappaateqalersinnaanermut annertuumik sunniuteqartunik akoqarput. Allannguutinik taamaattunik suussusersineq, pinngoqqaatinik nappaatinut patsisaasunik paasinnititseqataavoq, nunarsuarmilu nakorsaanermut nappatinillu suussusersiniaanermut atatillugu pinngoqqaatinik kingornuttakkanik misissuinermi naligiinnerulersitsilluni. Misissuinermi matumani, pinngoqqaatini allannguutinik, diabetesimik pinngoqqaammi akornuteqarnermik patsiseqartumi Maturity Onset Diabetes of the Young (MODY), Kalaallit Nunaanni innuttaasuni nalinginnaanerpaamit ilisimaneqartunik suussusersinissaq naliliinissarlu siunertaavoq. Innuttaasut katillugit 4497-it taakkunannga 448-it, pinngoqqaataat kingornuttakkat, pinngoqqaateqarfik tamakkerlugu misissukkat, kalaallit peqqissusaannik misissuisitsinernit paasissutissanik ataqatigiissitanik atuinikkut, pinngoqqaatit MODY-it ilisimaneqartut 14-it, ilisimaneqartunik ilisimaneqanngitsunillu allannguuteqarnersut misissorpagut. Allannguutip suussusersineqarlaap qanoq ittuuneranik nassuiaavugut, diabetisillu atugaaneranut uummalluuteqarnermullu inooriaatsimik patsiseqartumut ilisarnaatit innuttaasunilu diabetesimut atassutaa misissoqqissaarlugit. Naggueqatigiinni kalaallini pinngoqqaammi allannguut ilisimaneqartumi MODY- mi HNF1A maannamut suususersineqanngitsoq, pinngoqqaammi allannguut 1.9%-imik akulikissusilik, inuiannilu allani nassassaanngitsoq suussusersivarput. Pinngoqqaammi allannguutip pinngoqqaatip pissusissamisut allangornissaanik akornusiinera qanoq ittuuneranik misissuinerit paasinarsisippaat. Sukkumik arrortitsisinnaanermut misissuinermi pinngoqqaammi allannguutip 30-min insulinip appasinnerusarnera (β = −232 pmol/L, βSD = −0.695, P = 4.43 × 10−4) 30-min glucose-llu qaffasinnerunera (β = 1.20 mmol/L, βSD = 0.441, P = 0.0271) nassataraa. Allannguut type 2 diabetesimut (OR 4.35, P = 7.24 × 10−6) kiisalu HbA1c (β = 0.113 HbA1c%, βSD = 0.205, P = 7.84 × 10−3) atassuteqarpoq. Allannguutip Kalaallit Nunaanni diabetesimut allannguutip 2.5%-ia nassuiarpaa. Pinngoqqaammi allannguut nalunaarutigineqartoq pinngoqaammi MODY-mi allannguummit siornatigut nassuiarneqartumit innuttaasunut annertunerusumik sunniuteqarpoq. Pinngoqqaammi allannguut kinguaanit kingornunneqarsinnaasoq TBC1D4 ilanngullugu, Kalaallit Nunaanni diabetesimik nappaateqartut tallimaappata ataatsip pallingajattup (18%)- innuttaasunut amerlasuunut 1-3%-inut sanilliullugit-pinngoqqaammi allannguutinut nappaateqalernissamut annertuumik sunniutilinnut atassuteqarnera takutipparput. Novo Nordisk Fonden, Danmarks Frie Forskningsfond kiisalu Karen Elise Jensens Fond.”

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