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Exome Sequencing of 21 Bardet-Biedl Syndrome (BBS) Genes to Identify Obesity Variants in 6,851 American Indians.

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/m² ), 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.

SUBMITTER: Day SE

PROVIDER: S-EPMC8048836 | biostudies-literature |

REPOSITORIES: biostudies-literature

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