title: Whole-Exome Sequencing Suggests LAMB3 as a Susceptibility Gene for Morbid Obesity.
abstract: Identification of rare sequencing variants with a larger functional impact has the potential to highlight new pathways contributing to obesity. Using whole-exome sequencing followed by genotyping, we have identified a low-frequency coding variant rs2076349 (V527M) in the laminin subunit β3 (LAMB3) gene showing strong association with morbid obesity and thereby risk of type 2 diabetes. We exome-sequenced 200 morbidly obese subjects and 100 control subjects with pooled DNA samples. After several filtering steps, we retained 439 obesity-enriched low-frequency coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis of 1,911 morbidly obese and 1,274 control subjects, rs2076349 showed strong association with obesity (P = 9.67 × 10(-5); odds ratio 1.84). This variant was also associated with BMI and fasting serum leptin. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology (few but large fat cells). LAMB3 knockdown by small interfering RNA in human adipocytes cultured in vitro inhibited adipogenesis. In conclusion, we identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene. 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 Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden hong.jiao@ki.se ingrid.dahlman@ki.se.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.affiliation: Lipid Laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Agné
authors.initials: A
authors.lastname: Kulyté
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.affiliation: Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Thorell
authors.affiliation: Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Paul
authors.initials: P
authors.lastname: Gerdhem
authors.affiliation: Department of Biosciences and Nutrition, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: Lipid Laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.affiliation: Lipid Laboratory, Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden hong.jiao@ki.se ingrid.dahlman@ki.se.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
mesh_terms: D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000273:Adipose Tissue; D000328:Adult; D015992:Body Mass Index; D015815:Cell Adhesion Molecules / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005223:Fats / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D005223:Fats; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000097794:Kalinin