PuSH - Publikationsserver des Helmholtz Zentrums München

Bonnefond, A.* ; Clément, N.* ; Fawcett, K.* ; Yengo, L.* ; Vaillant, E.* ; Guillaume, J.L.* ; Dechaume, A.* ; Payne, F.* ; Roussel, R.* ; Czernichow, S.* ; Hercberg, S.* ; Hadjadj, S.* ; Balkau, B.* ; Marre, M.* ; Lantieri, O.* ; Langenberg, C.* ; Bouatia-Naji, N.* ; MAGIC Investigators (Grallert, H. ; Meisinger, C. ; Thorand, B. ; Wichmann, H.-E. ; Illig, T. ; Gieger, C.) ; Charpentier, G.* ; Vaxillaire, M.* ; Rocheleau, G.* ; Wareham, N.J.* ; Sladek, R.* ; McCarthy, M.I.* ; Dina, C.* ; Barroso, I.* ; Jockers, R.* ; Froguel, P.*

Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.

Nat. Genet. 44, 297-301 (2012)
Verlagsversion Volltext DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT(2)) increase type 2 diabetes (T2D) risk(1,2). Although the strongest association signal was highly significant (P < 1 × 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of ∼1.10-1.15)(1-3). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 × 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 × 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 × 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk.
Altmetric
Weitere Metriken?
Zusatzinfos bearbeiten [➜Einloggen]
Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Zeitschrift Nature Genetics
Quellenangaben Band: 44, Heft: 3, Seiten: 297-301 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed