title: Investigation of Genetic Variation Underlying Central Obesity amongst South Asians.
abstract: South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.|National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom.
authors.forename: William R
authors.initials: WR
authors.lastname: Scott
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.|Ealing Hospital NHS Trust, Southall, Middlesex, United Kingdom.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.
authors.forename: Marie
authors.initials: M
authors.lastname: Loh
authors.affiliation: National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom.|Ealing Hospital NHS Trust, Southall, Middlesex, United Kingdom.
authors.forename: Sian-Tsung
authors.initials: ST
authors.lastname: Tan
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lehne
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.
authors.forename: Uzma
authors.initials: U
authors.lastname: Afzal
authors.affiliation: Genomics Computer Centre, South Texas Diabetes and Obesity Institute, University of Texas at the Rio Grande Valley, Brownsville, Texas, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Peralta
authors.affiliation: Broad Institute of Massachusetts Institute of Technology and Harvard, Massachusetts General Hospital, Cambridge, MA, United States of America.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Hero DMC Heart Institute, Ludhiana, Punjab, India.
authors.forename: Sarju
authors.initials: S
authors.lastname: Ralhan
authors.affiliation: Hero DMC Heart Institute, Ludhiana, Punjab, India.
authors.forename: Gurpreet S
authors.initials: GS
authors.lastname: Wander
authors.affiliation: Genomics and Systems Biology, Baker IDI Heart and Diabetes Institute, Melbourne, VIC Australia.
authors.forename: Kiymet
authors.initials: K
authors.lastname: Bozaoglu
authors.affiliation: Department of Pediatrics, Section of Genetics, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.|Department of Pharmaceutical Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.|Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States of America.
authors.forename: Dharambir K
authors.initials: DK
authors.lastname: Sanghera
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.|MRC-PHE Centre for Environment and Health, Imperial College London, Norfolk Place, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Elliott
authors.affiliation: National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom.|Imperial College Healthcare NHS Trust, Du Cane Road, London, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Scott
authors.affiliation: Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom.|Ealing Hospital NHS Trust, Southall, Middlesex, United Kingdom.|MRC-PHE Centre for Environment and Health, Imperial College London, Norfolk Place, London, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.affiliation: National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London, United Kingdom.|Ealing Hospital NHS Trust, Southall, Middlesex, United Kingdom.|Imperial College Healthcare NHS Trust, Du Cane Road, London, United Kingdom.
authors.forename: Jaspal S
authors.initials: JS
authors.lastname: Kooner
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D044466:Asian People / Q000235:genetics; D059472:Exome; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000208:ethnology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics