title: Assessing variation across 8 established East Asian loci for type 2 diabetes mellitus in American Indians: Suggestive evidence for new sex-specific diabetes signals in GLIS3 and ZFAND3.
abstract: Eight new loci for type 2 diabetes mellitus (T2DM) were identified in an East Asian genome-wide association study meta-analysis. We assess tag SNPs across these loci for associations with T2DM in American Indians.
  
  
  
  A total of 435 SNPs that tag (R2≥ .85) common variation across the 8 loci were analyzed for association with T2DM (n = 7710), early onset T2DM (n = 1060), body mass index (n = 6839), insulin sensitivity (n = 555), and insulin secretion (n = 298).
  
  
  
  Tag SNPs within FITM2-R3HDML-HNF4A, GLIS3, KCNK16, and ZFAND3 associated with T2DM after accounting for locus-wide multiple testing. The T2DM association in FITM2-R3HDML-HNF4A (rs3212183; P = .0002; OR = 1.19 [1.09-1.30]) was independent from the East Asian lead SNP (rs6017317), which did not associate with T2DM in American Indians. The top signals in GLIS3 (rs7875253; P = .0004; OR = 1.23 [1.10-1.38]) and KCNK16 (rs1544050; P = .002; OR = 1.16 [1.06-1.27]) were attenuated after adjustment for the East Asian lead SNPs (rs7041847 in GLIS3; rs1535500 in KCNK16), both of which also associated with T2DM in American Indians (P = .02; OR = 1.11 [1.01-1.21]; P = .007; OR = 1.19 [1.05-1.36] respectively). The top SNP in ZFAND3 (rs9470794; P = .002; OR = 1.43 [1.14-1.80]) was the identical East Asian lead SNP. Additional SNPs in GLIS3 (rs180867004) and ZFAND3 (rs4714120 and rs9470701) had significant genotype × sex interactions (P ≤ .008). The GLIS3 SNP (rs180867004) associated with T2DM only in men (P = .00006, OR = 1.94 [1.40-2.68]). The ZFAND3 SNPs (rs4714120 and rs9470701) associated with T2DM only in women (P = .0002, OR = 1.35 [1.16-1.59]; P = .0003, OR = 1.37 [1.16-1.63] respectively).
  
  
  
  Replication of lead T2DM SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sex-specific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified.
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Yunhua L
authors.initials: YL
authors.lastname: Muller
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Paolo
authors.identifier: 0000-0003-2774-9161
authors.initials: P
authors.lastname: Piaggi
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Wiessner
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Chidinma
authors.initials: C
authors.lastname: Okani
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kobes
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Knowler
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Clifton
authors.initials: C
authors.lastname: Bogardus
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hanson
authors.affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Baier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins; D012737:Sex Factors; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C512851:GLIS3 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000604251:ZFAND4 protein, human
keywords: GLIS3; SNP; ZFAND3; established East Asian locus; sex-specific diabetes signal; type 2 diabetes mellitus