title: Exome array analysis identifies new loci and low-frequency variants influencing insulin processing and secretion.
abstract: Insulin secretion has a crucial role in glucose homeostasis, and failure to secrete sufficient insulin is a hallmark of type 2 diabetes. Genome-wide association studies (GWAS) have identified loci contributing to insulin processing and secretion; however, a substantial fraction of the genetic contribution remains undefined. To examine low-frequency (minor allele frequency (MAF) 0.5-5%) and rare (MAF < 0.5%) nonsynonymous variants, we analyzed exome array data in 8,229 nondiabetic Finnish males using the Illumina HumanExome Beadchip. We identified low-frequency coding variants associated with fasting proinsulin concentrations at the SGSM2 and MADD GWAS loci and three new genes with low-frequency variants associated with fasting proinsulin or insulinogenic index: TBC1D30, KANK1 and PAM. We also show that the interpretation of single-variant and gene-based tests needs to consider the effects of noncoding SNPs both nearby and megabases away. This study demonstrates that exome array genotyping is a valuable approach to identify low-frequency variants that contribute to complex traits.
authors.affiliation: Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Jeroen R
authors.initials: JR
authors.lastname: Huyghe
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.forename: Marie P
authors.initials: MP
authors.lastname: Fogarty
authors.forename: Martin L
authors.initials: ML
authors.lastname: Buchkovich
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stringham
authors.forename: Xueling
authors.initials: X
authors.lastname: Sim
authors.forename: Lingyao
authors.initials: L
authors.lastname: Yang
authors.forename: Christian
authors.initials: C
authors.lastname: Fuchsberger
authors.forename: Henna
authors.initials: H
authors.lastname: Cederberg
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Teslovich
authors.forename: Jane M
authors.initials: JM
authors.lastname: Romm
authors.forename: Hua
authors.initials: H
authors.lastname: Ling
authors.forename: Ivy
authors.initials: I
authors.lastname: McMullen
authors.forename: Roxann
authors.initials: R
authors.lastname: Ingersoll
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Neale
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Scott
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019760:Amidine-Lyases / Q000235:genetics; D003598:Cytoskeletal Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005215:Fasting / Q000097:blood; D005387:Finland; D005787:Gene Frequency; D014644:Genetic Variation; D005828:Genetics, Population; D005838:Genotype; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D058977:Molecular Sequence Annotation; D011384:Proinsulin / Q000097:blood; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C467739:KANK1 protein, human; C105852:MADD protein, human; C523295:SGSM2 protein, human; D025521:Tumor Suppressor Proteins; D011384:Proinsulin; D006899:Mixed Function Oxygenases; C544787:PAM protein, human; D019760:Amidine-Lyases