GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.
Vasiliki LagouLongda JiangAnna UlrichLiudmila ZudinaKarla Sofia Gutiérrez GonzálezZhanna BalkhiyarovaAlessia FaggianJared G MainaShiqian ChenPetar V TodorovSodbo SharapovAlessia DavidLetizia MarulloReedik MägiRoxana-Maria RujanEmma AhlqvistGudmar ThorleifssonΗe GaoEvangelos EvangelouBeben BenyaminRobert A ScottAaron IsaacsJing Hua ZhaoSara M WillemsToby JohnsonChristian GiegerHarald GrallertChrista MeisingerMartina Müller-NurasyidRona Juliette StrawbridgeAnuj GoelDenis RybinEva AlbrechtAnne U JacksonHeather M StringhamIvan R CorrêaEric H Farber-EgerValgerdur SteinthorsdottirAndre G UitterlindenPatricia B MunroeMorris J BrownJulian SchmidbergerOddgeir HolmenBarbara ThorandKristian HveemTom WilsgaardKaren L MohlkeZhe Wangnull nullAleksey ShmeliovMarcel den HoedRuth J F LoosWolfgang KratzerMark HaenleWolfgang KoenigBernhard O BoehmTricia M TanAlejandra TomasVictoria SalemInês A BarrosoJaakko TuomilehtoMichael BoehnkeJose C FlorezAnders HamstenHugh WatkinsInger NjølstadH-Erich WichmannMark J CaulfieldKay-Tee KhawCornelia M Van DuijnAlbert HofmanNicholas J WarehamClaudia LangenbergJohn B WhitfieldNicholas G MartinGrant W MontgomeryChiara ScapoliJoanna TzoulakiPaul ElliottUnnur ThorsteinsdottirKári StefánssonFrank E HarrellMark I McCarthyPhillippe FroguelPatrick M SextonDenise WoottenLeif C GroopJosée DupuisJames B MeigsGiuseppe DeganuttiAyse DemirkanTune H PersChristopher A ReynoldsYurii S AulchenkoMarika A KaakinenBen J JonesInga Prokopenkonull nullPublished in: Nature genetics (2023)
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification.
Keyphrases
- blood glucose
- glycemic control
- type diabetes
- molecular dynamics simulations
- genome wide
- lung function
- weight loss
- genome wide association
- cardiovascular disease
- genome wide association study
- blood pressure
- insulin resistance
- air pollution
- risk factors
- chronic obstructive pulmonary disease
- gene expression
- oxidative stress
- metabolic syndrome
- cystic fibrosis
- combination therapy
- high resolution
- copy number
- adipose tissue
- single molecule
- replacement therapy
- circulating tumor