Expressive

rs10875969 (NCKAP5L): BMI and Obesity Variant

Key takeaways

  • rs10875969 near NCKAP5L was identified as a candidate novel locus for BMI and extreme obesity in 6,645 Northern Nevada adults
  • The association has not been independently replicated and should be treated as preliminary evidence
  • GTEx data shows this variant is linked to altered expression of genes in skin, esophagus, thyroid, testis, brain, and prostate
  • The study combined genetics with electronic health records to identify both established and novel obesity loci

Key takeaways

  • rs10875969, near NCKAP5L, was identified as a candidate novel locus for BMI and extreme obesity in a single study of 6,645 adults from Northern Nevada.
  • The association has not been independently replicated in the available data and should be treated as preliminary.
  • GTEx tissue data links this variant to altered expression of several nearby genes across skin, esophagus, thyroid, testis, brain cerebellar hemisphere, and prostate.
  • The study combined genome-wide association testing with phenome-wide analysis tied to electronic health records, adding phenotypic context but not confirming causality.

What the research says A genome-wide association study (GWAS, a method that scans hundreds of thousands of genetic positions to find those statistically linked to a trait) of approximately 500,000 variants in 6,645 participants from the Healthy Nevada Project - a Northern Nevada cohort linked to electronic health records (EHR) - identified rs10875969, near the NCKAP5L gene (NCK-associated protein 5-like), as a candidate locus for BMI and obesity. Three parallel analyses were conducted: one restricted to participants without type 2 diabetes (DM2), one including DM2 as a comorbidity covariate, and a case-control analysis comparing extreme obesity (Class 2 or 3, BMI approximately 40 or above) against normal-weight controls (BMI 18.5-25). No specific beta coefficient or odds ratio for this locus was reported in the available study text.

Reported associations

  • BMI (non-diabetic cohort): Identified as a significant locus in a GWAS of BMI restricted to participants without type 2 diabetes in the Healthy Nevada cohort (n=6,645); specific effect size not reported in available text.
  • BMI (type 2 diabetes as covariate): Also identified as significant in a parallel GWAS including participants with type 2 diabetes modeled as a comorbid covariate (n=6,645); specific effect size not reported in available text.
  • Extreme obesity (Class 2/3): Identified in a case-control GWAS comparing extremely obese individuals (BMI approximately 40 or above) against normal-weight controls (BMI 18.5-25; n=6,645); specific effect size not reported in available text.

Evidence quality All three reported associations come from a single cohort study of 6,645 participants in the Healthy Nevada Project (Schlauch et al., G3, 2021), genotyped with the Illumina platform covering approximately 500,000 variants. No independent replication of this specific locus has been reported in the available data. The cohort is geographically concentrated in Northern Nevada, which may limit generalizability to broader populations. No specific p-value or effect size for this variant was included in the provided study text. The authors categorize some findings as "putative novel links," indicating this locus was not among previously established obesity variants at the time of publication. The study uses phenome-wide association analysis (PheWAS, a method that tests a single genetic variant against hundreds of clinical diagnoses simultaneously) alongside the GWAS to contextualize findings with EHR data, which adds phenotypic depth but does not constitute independent replication. Overall, the evidence for this variant should be considered preliminary and exploratory.

Tissue-specific expression effects

  • ENSG00000257253: The alternate allele is associated with increased expression in sun-exposed lower leg skin, non-sun-exposed suprapubic skin, and esophageal mucosa GTEx Portal.
  • C1QL4: The alternate allele is associated with increased expression in thyroid tissue GTEx Portal.
  • ENSG00000257464: The alternate allele is associated with reduced expression in testis and brain cerebellar hemisphere GTEx Portal.
  • BCDIN3D: The alternate allele is associated with reduced expression in prostate tissue GTEx Portal.
  • FAIM2: The alternate allele is associated with reduced expression in testis GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the NCKAP5L gene?

NCKAP5L (NCK-associated protein 5-like) is the gene nearest to the rs10875969 variant. It was flagged as a candidate site for BMI and obesity risk in a genome-wide association study of Northern Nevada adults. Its specific biological role in obesity has not been fully established in current research.

Is rs10875969 linked to obesity?

One study identified rs10875969, near NCKAP5L, as a candidate variant associated with BMI and extreme obesity in a cohort of 6,645 Northern Nevada adults. This finding has not yet been independently replicated in other populations, so it should be considered preliminary.

What does rs10875969 do to gene expression?

GTEx data shows the alternate allele at rs10875969 is associated with increased expression of nearby genes in skin and esophageal tissue, and reduced expression in testis, brain cerebellar hemisphere, and prostate. These are tissue-specific effects and their relationship to obesity risk has not been established.

What is a genome-wide association study (GWAS)?

A GWAS scans hundreds of thousands of genetic variants across the genome to find those that appear more often in people with a particular trait, such as high BMI. The study that identified rs10875969 tested approximately 500,000 variants in a Northern Nevada population of 6,645 participants.

Has rs10875969 been found in multiple studies?

The available evidence comes from a single study of 6,645 Northern Nevada adults published in the journal G3 in 2021. Independent replication of this specific variant in other populations has not been reported in the data provided.