title: Exome sequencing followed by genotyping suggests SYPL2 as a susceptibility gene for morbid obesity.
abstract: Recently developed high-throughput sequencing technology shows power to detect low-frequency disease-causing variants by deep sequencing of all known exons. We used exome sequencing to identify variants associated with morbid obesity. DNA from 100 morbidly obese adult subjects and 100 controls were pooled (n=10/pool), subjected to exome capture, and subsequent sequencing. At least 100 million sequencing reads were obtained from each pool. After several filtering steps and comparisons of observed frequencies of variants between obese and non-obese control pools, we systematically selected 144 obesity-enriched non-synonymous, splicing site or 5' upstream single-nucleotide variants for validation. We first genotyped 494 adult subjects with morbid obesity and 496 controls. Five obesity-associated variants (nominal P-value<0.05) were subsequently genotyped in 1425 morbidly obese and 782 controls. Out of the five variants, only rs62623713:A>G (NM_001040709:c.A296G:p.E99G) was confirmed. rs62623713 showed strong association with body mass index (beta=2.13 (1.09, 3.18), P=6.28 × 10(-5)) in a joint analysis of all 3197 genotyped subjects and had an odds ratio of 1.32 for obesity association. rs62623713 is a low-frequency (2.9% minor allele frequency) non-synonymous variant (E99G) in exon 4 of the synaptophysin-like 2 (SYPL2) gene. rs62623713 was not covered by Illumina or Affymetrix genotyping arrays used in previous genome-wide association studies. Mice lacking Sypl2 has been reported to display reduced body weight. In conclusion, using exome sequencing we identified a low-frequency coding variant in the SYPL2 gene that was associated with morbid obesity. This gene may be involved in the development of excess body fat.
authors.affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.affiliation: 1] Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden [2] CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Gerdhem
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rona J
authors.initials: RJ
authors.lastname: Strawbridge
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: 1] Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden [2] Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Thorell
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Department of Medicine (H7), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
mesh_terms: D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D016022:Case-Control Studies; D059472:Exome; D005091:Exons; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D016708:Synaptophysin / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; C000607848:SYPL2 protein, human; D016708:Synaptophysin; C100756:SYPL1 protein, human