title: Exome sequencing identifies a new candidate mutation for susceptibility to diabetes in a family with highly aggregated type 2 diabetes.
abstract: The aim of this study was to investigate the genetic background of familial clustering of diabetes using genome-wide linkage analysis combined with exome sequencing. We recruited a Japanese family with a 3-generation history of diabetes. The family comprised 16 members, 13 having been diagnosed with diabetes. Nine members had been diagnosed before the age of 40. Linkage analysis was performed assuming an autosomal dominant model. Linkage regions were observed on chromosomes 4q34, 5q11-q13, and 12p11-q22 and the logarithm of odds (LOD) scores were 1.80. To identify the susceptibility variants, we performed exome sequencing of an affected family member. We predicted that the familial clustering of diabetes is caused by a rare non-synonymous variant, and focused our analysis on non-synonymous variants absent in dbSNP131. Exome sequencing identified 10 such variants in the linkage regions, 7 of which were concordant with the affection status in the family. One hundred five normal subjects and 67 lean diabetes subjects were genotyped for the 7 variants; the only variant found to be significantly more frequent in the diabetes subjects than in the normal subjects was the N1072K variant of the early endosome antigen 1 (EEA1) gene (0 in normal subjects and 4 in diabetes subjects, p=0.022). We therefore propose that the N1072K variant of the EEA1 gene is a candidate mutation for susceptibility to diabetes in the Japanese population.
authors.affiliation: Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanaka
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagashima
authors.forename: Mayumi
authors.initials: M
authors.lastname: Sasaki
authors.forename: Shogo
authors.initials: S
authors.lastname: Funakoshi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kondo
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yasuda
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology; D059472:Exome / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1