A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family

Habiba S. Al Safar; Heather J. Cordell; Osman Jafer; Denise Anderson; Sarra E. Jamieson; Michaela Fakiola; Kamal Khazanehdari; Guan K. Tay; Jenefer M. Blackwell

doi:10.1111/ahg.12036

A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family

Habiba S. Al Safar
, Heather J. Cordell
, Osman Jafer
, Denise Anderson
, Sarra E. Jamieson
, Michaela Fakiola
, Kamal Khazanehdari
, Guan K. Tay
, Jenefer M. Blackwell

Biomedical Engineering & Biotechnology

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P = 5 × 10^-8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P = 9.70 × 10^-6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10^-6) and 14q13 (PRKD1: rs10144903, 3.92 × 10^-6), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, P_adj-agesex = 2.06 × 10^-5; KCTD8: rs4407541, P_adj-agesex = 1.42 × 10^-4; GABRB1: rs10517178/rs1372491, P_adj-agesex = 0.027; 14q13 PRKD1: rs10144903, P_adj-agesex = 6.95 × 10^-5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (P_adj-agesex = 0.030) and rs2055942 (P_adj-agesex =0.022) atCOX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: P_adj-agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: P_{adj-agesex-combined} = 3 × 10^-4) and at KCTD8 (rs4695718: P_{adj-agesex-combined} = 2 × 10^-4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; P_adj-agesex = 0.031; P_{adj-agesex-combined} = 2 × 10^-4). These genes may provide important functional leads in understanding disease pathogenesis in this population.

Original language	British English
Pages (from-to)	488-503
Number of pages	16
Journal	Annals of Human Genetics
Volume	77
Issue number	6
DOIs	https://doi.org/10.1111/ahg.12036
State	Published - Nov 2013

Keywords

Association analysis
Family-based GWAS
Type 2 diabetes
UAE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1111/ahg.12036

Cite this

@article{a5745b22775d403fb0f1f02418ee87e7,

title = "A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family",

abstract = "Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P = 5 × 10-8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P = 9.70 × 10-6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10-6) and 14q13 (PRKD1: rs10144903, 3.92 × 10-6), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, Padj-agesex = 2.06 × 10-5; KCTD8: rs4407541, Padj-agesex = 1.42 × 10-4; GABRB1: rs10517178/rs1372491, Padj-agesex = 0.027; 14q13 PRKD1: rs10144903, Padj-agesex = 6.95 × 10-5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj-agesex = 0.030) and rs2055942 (Padj-agesex =0.022) atCOX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj-agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj-agesex-combined = 3 × 10-4) and at KCTD8 (rs4695718: Padj-agesex-combined = 2 × 10-4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj-agesex = 0.031; Padj-agesex-combined = 2 × 10-4). These genes may provide important functional leads in understanding disease pathogenesis in this population.",

keywords = "Association analysis, Family-based GWAS, Type 2 diabetes, UAE",

author = "\{Al Safar\}, \{Habiba S.\} and Cordell, \{Heather J.\} and Osman Jafer and Denise Anderson and Jamieson, \{Sarra E.\} and Michaela Fakiola and Kamal Khazanehdari and Tay, \{Guan K.\} and Blackwell, \{Jenefer M.\}",

year = "2013",

month = nov,

doi = "10.1111/ahg.12036",

language = "British English",

volume = "77",

pages = "488--503",

journal = "Annals of Human Genetics",

issn = "0003-4800",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "6",

}

TY - JOUR

T1 - A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family

AU - Al Safar, Habiba S.

AU - Cordell, Heather J.

AU - Jafer, Osman

AU - Anderson, Denise

AU - Jamieson, Sarra E.

AU - Fakiola, Michaela

AU - Khazanehdari, Kamal

AU - Tay, Guan K.

AU - Blackwell, Jenefer M.

PY - 2013/11

Y1 - 2013/11

N2 - Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P = 5 × 10-8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P = 9.70 × 10-6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10-6) and 14q13 (PRKD1: rs10144903, 3.92 × 10-6), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, Padj-agesex = 2.06 × 10-5; KCTD8: rs4407541, Padj-agesex = 1.42 × 10-4; GABRB1: rs10517178/rs1372491, Padj-agesex = 0.027; 14q13 PRKD1: rs10144903, Padj-agesex = 6.95 × 10-5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj-agesex = 0.030) and rs2055942 (Padj-agesex =0.022) atCOX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj-agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj-agesex-combined = 3 × 10-4) and at KCTD8 (rs4695718: Padj-agesex-combined = 2 × 10-4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj-agesex = 0.031; Padj-agesex-combined = 2 × 10-4). These genes may provide important functional leads in understanding disease pathogenesis in this population.

AB - Twenty percent of people aged 20 to 79 have type 2 diabetes (T2D) in the United Arab Emirates (UAE). Genome-wide association studies (GWAS) to identify genes for T2D have not been reported for Arab countries. We performed a discovery GWAS in an extended UAE family (N = 178; 66 diabetic; 112 healthy) genotyped on the Illumina Human 660 Quad Beadchip, with independent replication of top hits in 116 cases and 199 controls. Power to achieve genome-wide significance (commonly P = 5 × 10-8) was therefore limited. Nevertheless, transmission disequilibrium testing in FBAT identified top hits at Chromosome 4p12-p13 (KCTD8: rs4407541, P = 9.70 × 10-6; GABRB1: rs10517178/rs1372491, P = 4.19 × 10-6) and 14q13 (PRKD1: rs10144903, 3.92 × 10-6), supported by analysis using a linear mixed model approximation in GenABEL (4p12-p13 GABRG1/GABRA2: rs7662743, Padj-agesex = 2.06 × 10-5; KCTD8: rs4407541, Padj-agesex = 1.42 × 10-4; GABRB1: rs10517178/rs1372491, Padj-agesex = 0.027; 14q13 PRKD1: rs10144903, Padj-agesex = 6.95 × 10-5). SNPs across GABRG1/GABRA2 did not replicate, whereas more proximal SNPs rs7679715 (Padj-agesex = 0.030) and rs2055942 (Padj-agesex =0.022) atCOX7B2/GABRA4 did, in addition to a trend distally at KCTD8 (rs4695718: Padj-agesex = 0.096). Modelling of discovery and replication data support independent signals at GABRA4 (rs2055942: Padj-agesex-combined = 3 × 10-4) and at KCTD8 (rs4695718: Padj-agesex-combined = 2 × 10-4). Replication was observed for PRKD1 rs1953722 (proxy for rs10144903; Padj-agesex = 0.031; Padj-agesex-combined = 2 × 10-4). These genes may provide important functional leads in understanding disease pathogenesis in this population.

KW - Association analysis

KW - Family-based GWAS

KW - Type 2 diabetes

KW - UAE

UR - https://www.scopus.com/pages/publications/84893024690

U2 - 10.1111/ahg.12036

DO - 10.1111/ahg.12036

M3 - Article

C2 - 23937595

AN - SCOPUS:84893024690

SN - 0003-4800

VL - 77

SP - 488

EP - 503

JO - Annals of Human Genetics

JF - Annals of Human Genetics

IS - 6

ER -

A genome-wide search for type 2 diabetes susceptibility genes in an extended Arab family

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this