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Title: Exome sequencing reveals novel genetic loci influencing obesity-related traits in Hispanic children

Author
item SABO, ANIKO - Baylor College Of Medicine
item MISHRA, PAMELA - Baylor College Of Medicine
item DUGAN-PEREZ, SHANNON - Baylor College Of Medicine
item VORUGANTI, V. SAROJA - University Of North Carolina
item KENT JR, JACK - Texas Biomedical Institute
item KALRA, DIVYA - Baylor College Of Medicine
item COLE, SHELLEY - Texas Biomedical Institute
item COMUZZIE, ANTHONY - Texas Biomedical Institute
item MUZNY, DONNA - Baylor College Of Medicine
item GIBBS, RICHARD - Baylor College Of Medicine
item BUTTE, NANCY - Children'S Nutrition Research Center (CNRC)

Submitted to: Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/30/2017
Publication Date: 5/16/2017
Citation: Sabo, A., Mishra, P., Dugan-Perez, S., Voruganti, V., Kent Jr, J.W., Kalra, D., Cole, S.A., Comuzzie, A.G., Muzny, D.M., Gibbs, R.A., Butte, N.F. 2017. Exome sequencing reveals novel genetic loci influencing obesity-related traits in Hispanic children. Obesity. doi:10.1002/oby.21869.

Interpretive Summary: Childhood obesity is caused by both environmental and genetic factors, and yet identification of the genetic factors remains elusive. In this study, whole exome sequencing was performed on 928 Hispanic children to identify variation in the protein-coding segments of their DNA. Relationships between variation identified in single nucleotide variants (SNVs) and 74 obesity-related traits in the children were analyzed using genetic statistical programs. The principal findings from this study were 1) rare variants in 10 genes and 16 common variants in 11 genes; 2) newly discovered variants in a gene called peroxisome biogenesis factor 1 (PEX1) was strongly related to obesity characteristics; 3) previously reported variants were duplicated. In conclusion, this exome sequencing project revealed novel findings contributing to childhood obesity in the Hispanic population.

Technical Abstract: To perform whole exome sequencing in 928 Hispanic children and identify variants and genes associated with childhood obesity.Single-nucleotide variants (SNVs) were identified from Illumina whole exome sequencing data using integrated read mapping, variant calling, and an annotation pipeline (Mercury). Association analyses of 74 obesity-related traits and exonic variants were performed using SeqMeta software. Rare autosomal variants were analyzed using gene-based association analyses, and common autosomal variants were analyzed at the SNV level. (1) Rare exonic variants in 10 genes and 16 common SNVs in 11 genes that were associated with obesity traits in a cohort of Hispanic children were identified, (2) novel rare variants in peroxisome biogenesis factor 1 (PEX1) associated with several obesity traits (weight, weight z score, BMI, BMI z score, waist circumference, fat mass, trunk fat mass) were discovered, and (3) previously reported SNVs associated with childhood obesity were replicated.Convergence of whole exome sequencing, a family-based design, and extensive phenotyping discovered novel rare and common variants associated with childhood obesity. Linking PEX1 to obesity phenotypes poses a novel mechanism of peroxisomal biogenesis and metabolism underlying the development of childhood obesity.