Expressive

rs11983537 (CCDC146): Brain Amyloid Deposition Variant

Key takeaways

  • rs11983537 on chromosome 7 was linked to reduced brain amyloid-beta in a 1,474-person Korean genome-wide study.
  • The finding was replicated in a second cohort but did not reach the gold-standard genome-wide significance threshold on its own.
  • Evidence is preliminary, limited to Korean-ancestry adults, and has not been independently replicated at genome-wide significance.
  • GTEx data show this variant is linked to altered expression of GSAP, PMS2P9, APTR, and ENSG00000305531 across brain, blood, and gut tissues.
  • No drug-response or lifestyle data are currently linked to this specific variant.

Key takeaways

  • rs11983537 on chromosome 7 was associated with reduced brain amyloid-beta deposition in a genome-wide study of 1,474 Korean adults.
  • The finding was replicated in an independent Korean cohort at p < 0.05 but did not reach the standard genome-wide significance threshold (p < 5 x 10^-8).
  • Evidence is preliminary and comes from a single Korean-ancestry study; applicability to other populations is unknown.
  • The alternate allele is also linked to altered expression of multiple genes including GSAP and APTR across brain, blood, and digestive tissues.
  • No drug-response or lifestyle data are currently associated with this specific variant.

What the research says rs11983537 is one of four novel single-nucleotide polymorphisms (SNPs - single-letter changes in DNA) on chromosome 7 identified at a genome-wide suggestive level in a GWAS of 1,190 Korean adults as associated with decreased likelihood of amyloid-beta positivity, a biomarker for early Alzheimer's disease pathology measured via amyloid PET imaging. The association was then examined in an independent replication cohort of 284 Korean participants, where this variant reached nominal significance (p < 0.05). Unlike two other chromosome 7 SNPs in the same study (rs7337542 and rs2903923), this locus did not reach the conventional genome-wide significance threshold of p < 5 x 10^-8 in meta-analysis, placing it in the category of suggestive but not conclusively established associations.

Reported associations

  • Brain amyloid-beta positivity (Alzheimer's disease pathway): Associated with decreased risk of amyloid-beta positivity by amyloid PET imaging in a Korean GWAS (discovery n = 1,190; replication n = 284); the association was genome-wide suggestive in discovery and p < 0.05 in replication, but did not reach genome-wide significance in meta-analysis.
  • GSAP gene expression in cultured fibroblasts: The alternate allele is associated with reduced GSAP expression in cultured fibroblasts GTEx Portal.
  • GSAP gene expression in whole blood: The alternate allele is associated with increased GSAP expression in whole blood GTEx Portal.
  • ENSG00000305531 gene expression in esophagus mucosa: The alternate allele is associated with increased expression of ENSG00000305531 in esophagus mucosa GTEx Portal.
  • PMS2P9 gene expression in intestinal and pituitary tissues: The alternate allele is associated with increased PMS2P9 expression in the small intestine (terminal ileum), pituitary gland, sigmoid colon, and transverse colon GTEx Portal.
  • APTR gene expression in brain nucleus accumbens: The alternate allele is associated with increased APTR expression in the nucleus accumbens of the basal ganglia GTEx Portal.

Evidence quality The sole genomic association evidence for this variant comes from one study of 1,474 Korean-ancestry participants (discovery n = 1,190; replication n = 284). rs11983537 met only a genome-wide suggestive threshold in discovery and a nominal p < 0.05 in replication; it did not achieve the conventional cutoff of p < 5 x 10^-8 in meta-analysis. The two chromosome 7 SNPs that did reach that threshold in the same study (rs7337542 and rs2903923) are distinct variants from this locus. The study is limited to Korean ancestry and no replication in other ethnic groups is reported in the available data. GTEx eQTL data (953 donors, FDR < 0.05) provide mechanistic context on tissue-level gene expression but do not constitute clinical outcome evidence. Notably, GSAP expression effects run in opposite directions in fibroblasts (reduced) versus whole blood (increased), representing a conflicting-direction finding across tissue types.

Tissue-specific expression effects

  • GSAP: The alternate allele is linked to reduced expression in cultured fibroblasts and increased expression in whole blood, showing opposite-direction effects across these two tissue types GTEx Portal.
  • ENSG00000305531: The alternate allele is linked to increased expression in esophagus mucosa GTEx Portal.
  • PMS2P9: The alternate allele is linked to increased expression in small intestine (terminal ileum), pituitary gland, sigmoid colon, and transverse colon GTEx Portal.
  • APTR: The alternate allele is linked to increased expression in the nucleus accumbens of the brain's basal ganglia GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs11983537?

rs11983537 is a genetic variant on chromosome 7, located near the CCDC146 gene. It was identified in a Korean population genome-wide study as tentatively associated with lower levels of amyloid-beta protein in the brain, which is an early marker of Alzheimer's disease pathology.

Is rs11983537 linked to Alzheimer's disease?

A genome-wide study of 1,474 Korean adults found rs11983537 was associated with a reduced likelihood of testing positive for brain amyloid-beta deposits, which are an early feature of Alzheimer's disease. The evidence is preliminary: the variant did not reach the gold-standard genome-wide significance threshold, and findings have not been replicated in non-Korean populations based on available data.

What population was rs11983537 studied in?

The available evidence comes from a multi-center study of Korean adults in South Korea, with a discovery cohort of 1,190 participants and a separate replication cohort of 284. No data from non-Korean populations are available in the provided studies.

Does rs11983537 affect gene expression?

Yes, according to GTEx eQTL data from 953 donors, the alternate allele is linked to reduced GSAP expression in fibroblasts but increased GSAP expression in whole blood (opposite directions), increased APTR expression in brain nucleus accumbens, increased PMS2P9 expression in intestinal and pituitary tissues, and increased ENSG00000305531 expression in esophagus tissue. These are tissue-level expression associations, not clinical outcomes.

What is the CCDC146 gene?

CCDC146 is the gene near rs11983537 on chromosome 7. The study providing evidence for this variant does not describe the specific function of CCDC146 in relation to amyloid-beta; the study's primary molecular finding centered on a nearby variant in the same chromosomal region that was linked to FGL2 gene expression in the brain.