rs10842707 (SSPN-AS1): Body Fat Distribution Variant

Key takeaways

• rs10842707 has been studied in GWAS of waist-to-hip ratio adjusted for BMI (WHRadjBMI), with the largest study covering nearly 700,000 adults.
• The variant is linked to higher BHLHE41 expression in skin, fibroblasts, and pancreas, pointing to a tissue-specific regulatory mechanism.
• In the largest WHRadjBMI meta-analysis, the top 5% of risk-allele carriers were 1.62 times more likely to exceed metabolic-syndrome waist-to-hip thresholds than the bottom 5%.
• Sex-specific effects on body fat distribution are prominent here; 28 of 44 sex-dimorphic WHRadjBMI loci showed stronger effects in women than in men.
• All 463 identified signals in the largest WHRadjBMI study together explained only 3.9% of phenotypic variance, illustrating the small effect of any single variant.

What the research says A meta-analysis of WHRadjBMI in 694,649 European-ancestry adults identified 463 independent signals across 346 loci, explaining approximately 3.9% of phenotypic variance, with roughly one-third of signals showing sexually dimorphic effects PMID 30325407. A GWAS in 241,258 adults accounting for tobacco smoking identified 23 novel obesity-related loci and 9 loci with significant gene-by-smoking interactions, indicating that smoking may modify genetic susceptibility to central fat distribution and overall adiposity PMID 30482895. A trans-ancestral GWAS in Hispanic/Latino adults (n=59,771 stage 1, n=10,538 stage 2) combined with European- and African-ancestry summary statistics identified 42 novel genomic findings for BMI, height, and WHRadjBMI, demonstrating that diverse-ancestry cohorts improve discovery and fine-mapping precision.

Reported associations

• WHRadjBMI: Identified in a large-scale European-ancestry meta-analysis (n=694,649); across all 463 associated loci, individuals in the top 5% for risk-allele burden were 1.62 times more likely to exceed metabolic-syndrome WHR thresholds than those in the bottom 5% PMID 30325407.
• WHRadjBMI with sex-specific effects: A genome-wide interaction meta-analysis in up to 320,485 individuals found 44 WHRadjBMI loci with sex-specific effects; 28 showed larger effects in women, 5 showed larger effects in men, and 11 showed opposite-direction effects between sexes PMID 26833246.
• WHRadjBMI with smoking interaction: A GWAS adjusting for smoking in 241,258 adults found 6 novel WHRadjBMI loci and 5 WHRadjBMI loci with significant gene-by-smoking interaction effects PMID 30482895.
• BMI with age-specific effects: In a genome-wide interaction meta-analysis of up to 320,485 individuals, 15 BMI loci showed age-dependent effects; 11 had larger effects in adults under 50 than in those aged 50 or older PMID 26833246.
• Adiposity with physical activity interaction: A genome-wide meta-analysis in up to 200,452 adults identified 11 novel adiposity loci when adjusting for physical activity; the FTO locus BMI-increasing effect was attenuated by approximately 30% in physically active versus inactive individuals PMID 28448500.
• Allometric body shape indices: A GWAS in 219,872 women and 186,825 men in UK Biobank using ABSI, Hip Index, and Waist-to-Hip Index found that one- to two-thirds of identified loci were novel relative to traditional BMI-adjusted measures PMID 33568684.
• Shared genetics of BMI and later-onset asthma: A cross-trait GWAS of 457,822 European-ancestry individuals found 34 shared loci between obesity-related traits and asthma subtypes; the genetic correlation between BMI and later-onset asthma was Rg=0.25 (p=9.56x10-22), with Mendelian randomization supporting a causal effect of BMI on asthma risk PMID 32315725.
• Educational attainment: A GWAS in approximately 3 million individuals identified 3,952 genome-wide-significant SNPs; a polygenic index for this trait explained 12-16% of educational attainment variance and added predictive power for ten diseases PMID 35637425.

Evidence quality The WHRadjBMI and BMI associations draw on some of the largest GWAS conducted for anthropometric traits, covering 694,649 participants in the primary body-fat-distribution analysis PMID 30325407 and more than 300,000 in sex- and age-interaction analyses PMID 26833246. The smoking-interaction GWAS used directional consistency across independent cohorts as a validation step PMID 30482895, and the physical-activity-interaction study applied a comparable cross-cohort approach PMID 28448500. Trans-ancestral replication in Hispanic/Latino populations adds cross-population support for some loci, though this component was conducted primarily as a discovery analysis rather than strict independent replication. The educational attainment GWAS PMID 35637425 is the largest by sample size but covers a distinct phenotypic domain; the biological pathway connecting this locus to educational attainment is not addressed in the provided studies. All individual-variant effect sizes for these complex traits are small, and no functional experiments directly validating the causal transcript at this locus are reported in the provided evidence.

Tissue-specific expression effects

• BHLHE41: The alternate allele is associated with increased BHLHE41 expression in pancreas, cultured fibroblasts, and both sun-exposed and non-sun-exposed skin GTEx Portal.
• ENSG00000286752: Increased expression of this gene is observed in testis and heart atrial appendage GTEx Portal.
• ENSG00000256894: Increased expression is observed in sun-exposed and non-sun-exposed skin GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.