Expressive

rs12444979 (GPRC5B): body weight genetics

Key takeaways

  • rs12444979 near GPRC5B was one of 18 new genome-wide significant BMI loci identified in nearly 250,000 people
  • The locus contains a copy number variant, a section of DNA present in varying numbers of copies between individuals
  • BMI polygenic scores associate with 316 clinical diagnoses in a large biobank, 96.5% of which show increased risk
  • Shared genetic architecture links BMI loci as a class to ADHD, depression, and other psychiatric conditions
  • This variant raises expression of KNOP1 in fat and muscle tissue, offering a potential molecular mechanism near the locus

Key takeaways

  • rs12444979, between the GPRC5B and GPR139 receptor genes, was first linked to body mass index (BMI) as one of 18 novel genome-wide significant loci in a study of nearly 250,000 individuals.
  • The locus includes a copy number variant near GPRC5B, a structural change where a segment of DNA can occur in varying numbers of copies between people.
  • Large-scale BMI genetics research now encompasses 906 genome-wide significant loci in over one million individuals, placing this region within a broadly replicated genetic architecture.
  • Shared genetic architecture connects BMI-associated loci as a class to psychiatric conditions including attention-deficit/hyperactivity disorder and major depressive disorder.
  • In adipose and skeletal muscle tissue, this variant is associated with increased expression of KNOP1, a nucleolar protein gene adjacent to the locus.

What the research says rs12444979, near GPRC5B (G Protein-Coupled Receptor Class C Group 5 Member B) and GPR139, was identified as one of six genomic loci not previously associated with any obesity-related trait, first reaching genome-wide significance (P < 5 x 10^-8) in a meta-analysis of up to 123,865 individuals and confirmed in a joint analysis of up to 249,796 individuals of European ancestry; the signal at this locus involves a copy number variant near GPRC5B, and effect sizes for newly discovered loci in that analysis were described as slightly smaller on average than those of previously established BMI variants. PMID 20935630 In a separate large-scale analysis of approximately 1.1 million individuals of European ancestry, 906 genome-wide significant BMI loci were identified, and a polygenic score built from 2,446 BMI variants was associated with 316 clinical diagnoses in the Million Veteran Program, 96.5% of which showed increased risk across a broad range of organ systems. PMID 36849438 A cross-trait genome-wide analysis using European-ancestry GWAS summary data (sample sizes ranging from 9,725 to 500,199 across constituent studies) replicated 211 previously reported obesity loci and found 58 novel loci shared between obesity classes and psychiatric disorders including ADHD, autism spectrum disorder, anorexia nervosa, major depressive disorder, schizophrenia, and obsessive-compulsive disorder, with Mendelian randomization suggesting potential causal links in one or both directions. PMID 35908544

Reported associations

  • Body mass index: One of 18 novel genome-wide significant loci (P < 5 x 10^-8) for BMI, confirmed in a joint meta-analysis of up to 249,796 individuals of European ancestry; the locus includes a copy number variant near GPRC5B, and effect sizes were slightly smaller on average than those of previously established BMI variants. PMID 20935630
  • Body mass index (large-scale landscape): Part of an expanded architecture of 906 genome-wide significant BMI loci identified in approximately 1.1 million individuals of European ancestry and 41 loci in approximately 100,000 individuals of African ancestry. PMID 36849438
  • BMI-related disease burden: A polygenic score built from 2,446 BMI variants was associated with 316 clinical diagnoses in the Million Veteran Program, 96.5% showing increased risk, spanning circulatory, genitourinary, respiratory, musculoskeletal, and dermatologic conditions. PMID 36849438
  • Shared genetics with psychiatric disorders: Cross-trait analysis identified shared genomic loci between obesity classes and ADHD, autism spectrum disorder, anorexia nervosa, major depressive disorder, schizophrenia, and obsessive-compulsive disorder; Mendelian randomization suggested potential two-way or one-way causal relationships. PMID 35908544

Evidence quality The BMI association at the GPRC5B - GPR139 locus reached genome-wide significance (P < 5 x 10^-8) in a two-stage meta-analysis totaling up to 249,796 individuals of European ancestry, meeting the conventional threshold for robust GWAS association. PMID 20935630 The broader BMI genetic landscape was further interrogated in approximately 1.1 million individuals, though the available data do not report a specific per-locus effect size (beta coefficient or odds ratio) for rs12444979 itself. PMID 36849438 The psychiatric overlap findings rely on cross-trait GWAS and Mendelian randomization using European-ancestry summary data with sample sizes ranging from 9,725 to 500,199 across constituent studies; this evidence implicates BMI loci as a class rather than rs12444979 individually, and should be treated as preliminary for this specific variant. PMID 35908544 No conflicting findings are reported across these studies.

Tissue-specific expression effects

  • KNOP1: This variant is associated with increased expression of KNOP1 (a gene encoding a lysine-rich nucleolar protein, located adjacent to the GPRC5B - GPR139 locus) across subcutaneous adipose tissue, visceral adipose tissue, skeletal muscle, tibial nerve, heart atrial appendage, esophagus muscularis, and two skin tissue types (sun-exposed lower leg and non-sun-exposed suprapubic). GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is GPRC5B?

GPRC5B, short for G Protein-Coupled Receptor Class C Group 5 Member B, is a cell-surface receptor protein. It belongs to the large GPCR family that helps cells sense and respond to molecular signals, and genetic variation near this gene has been linked to body weight in large population studies.

Is rs12444979 linked to obesity?

Yes. rs12444979, near GPRC5B and GPR139, was identified as one of 18 novel genomic loci significantly associated with body mass index in a study of up to 249,796 individuals of European ancestry. The association has since been replicated in much larger datasets of over one million individuals.

What is a copy number variant?

A copy number variant is a stretch of DNA that can be present in different numbers of copies in different individuals, rather than the usual two copies. The rs12444979 region includes a copy number variant near GPRC5B, which can influence how nearby genes behave.

Does rs12444979 affect gene expression?

GTEx data shows that this variant is linked to increased activity of a nearby gene called KNOP1 across multiple tissue types, including subcutaneous fat, visceral fat, skeletal muscle, and heart tissue.

Is this variant connected to mental health conditions?

Research finds shared genetic signals between BMI-associated loci as a group and conditions including ADHD and major depressive disorder. Whether rs12444979 specifically contributes to this overlap has not been individually established in the available studies.