Exome Sequencing of 21 Bardet‐Biedl Syndrome (BBS) Genes to Identify Obesity Variants in 6, 851 American Indians. Issue 4 (22nd February 2021)

• Record Type: Journal Article
• Authors: Day, Samantha E.; Muller, Yunhua L.; Koroglu, Cigdem; Kobes, Sayuko; Wiedrich, Kim; Mahkee, Darin; Kim, Hye In; Van Hout, Cris; Gosalia, Nehal; Ye, Bin; Shuldiner, Alan R.; Knowler, William C.; Hanson, Robert L.; Bogardus, Clifton; Baier, Leslie J.
• Is Part Of: Obesity. Volume 29:Issue 4(2021)
• Page Start: 748
• Page End: 754
• Publication Date: 2021-02-22
• Subjects: Obesity -- Periodicals; 616.398005
• DOI: 10.1002/oby.23115
• Languages: English
• ISSNs: 1930-7381

Abstract

Abstract : Objective: In an ongoing effort to identify the genetic variation that contributes to obesity in American Indians, known Bardet–Biedl syndrome (BBS) genes were analyzed for an effect on BMI and leptin signaling. Methods: Potentially deleterious variants (Combined Annotation Dependent Depletion score > 20) in BBS genes were identified in whole‐exome sequence data from 6, 851 American Indians informative for BMI. Common variants (detected in ≥ 10 individuals) were analyzed for association with BMI; rare variants (detected in < 10 individuals) were analyzed for mean BMI of carriers. Functional assessment of variants' effect on signal transducer and activator of transcription 3 (STAT3) activity was performed in vitro . Results: One common variant, rs59252892 (Thr549Ile) in BBS9, was associated with BMI ( P = 0.0008, β = 25% increase per risk allele). Among rare variants for which carriers had severe obesity (mean BMI > 40 kg/m 2 ), four were in BBS9 . In vitro analysis of BBS9 found the Ile allele at Thr549Ile had a 20% increase in STAT3 activity compared with the Thr allele ( P = 0.01). Western blot analysis showed the Ile allele had a 15% increase in STAT3 phosphorylation ( P = 0.006). Comparable functional results were observed with Ser545Gly and Val209Leu but not Leu665Phe and Lys810Glu. Conclusions: Potentially functional variants in BBS genes in American Indians are reported. However, functional evidence supporting a causal role for BBS9 in obesity is inconclusive.