Expressive

rs11731003 (SORCS2): Alcohol Withdrawal Risk

Key takeaways

  • rs11731003 in SORCS2, a brain-expressed neurotrophin receptor gene, reached genome-wide significance (p = 4.3 x 10^-9) for alcohol withdrawal symptom count in 1,478 European-American adults.
  • The risk variant is predicted to disrupt a regulatory element controlled by stress hormones in the human hippocampus.
  • SORCS2 expression increases in neural cells during both ethanol exposure and withdrawal, suggesting a direct biological connection.
  • No genome-wide significant signal was found in 1,231 African-American participants, so this finding may not apply equally across all ancestries.
  • GTEx data show this variant also boosts SORCS2 expression in esophageal muscularis tissue.

Key takeaways

  • rs11731003 in SORCS2, a brain-expressed neurotrophin receptor gene, reached genome-wide significance (p = 4.3 x 10^-9) for alcohol withdrawal symptom count in 1,478 European-American adults.
  • The risk variant is predicted to disrupt a regulatory element controlled by stress hormones in the human hippocampus.
  • SORCS2 expression increases in neural cells during both ethanol exposure and withdrawal, suggesting a direct biological connection.
  • No genome-wide significant signal was found in 1,231 African-American participants, so this finding may not apply equally across all ancestries.
  • GTEx data show this variant also boosts SORCS2 expression in esophageal muscularis tissue.

What the research says A genome-wide association study (GWAS) of alcohol withdrawal (AW) symptom count identified rs11731003, located in SORCS2 (sortilin-related VPS10 domain-containing receptor 2, a sortilin-family neurotrophin receptor gene on chromosome 4), as the top association signal in a European-American meta-analysis (n = 1,478, p = 4.3 x 10^-9) PMID 31136012. The risk haplotype at this locus is predicted to disrupt a stress hormone-modulated regulatory element with tissue-specific activity in human hippocampus, and in vitro experiments in human neural lineage cells confirmed that stress hormone levels can alter expression of this gene PMID 31136012. SORCS2 expression in culture increased upon both ethanol exposure and withdrawal, providing a mechanistic link between the variant and AW biology PMID 31136012.

Reported associations

  • Alcohol withdrawal symptom count (European-American): Genome-wide significant association (p = 4.3 x 10^-9) for number of AW symptoms in a meta-analysis of 1,478 adults with histories of serious alcohol withdrawal PMID 31136012
  • Alcohol withdrawal symptom count (African-American): No genome-wide significant findings in 1,231 African-American individuals assessed with the same protocol PMID 31136012

Evidence quality The association rests on a single published GWAS and meta-analysis in a European-American cohort (n = 1,478), supplemented by additional independent genotyping in separate AW subjects that contributed to the meta-analysis total PMID 31136012. The p-value of 4.3 x 10^-9 falls below the conventional genome-wide significance threshold of 5 x 10^-8, providing strong statistical support in this population PMID 31136012. No genome-wide significant results were observed in the African-American cohort (n = 1,231), which may reflect true population differences, limited statistical power, or both PMID 31136012. Bioinformatic and in vitro evidence supports a mechanistic pathway through stress hormone regulation in hippocampal tissue, but the total discovery sample is modest by current GWAS standards, and the study does not report an independent full replication in a separate published dataset PMID 31136012.

Tissue-specific expression effects

  • SORCS2: The ALT allele is associated with increased expression in esophageal muscularis tissue (GTEx v11, 953 donors, p = 2.5 x 10^-5) GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is SORCS2 and what does it do?

SORCS2 encodes sortilin-related VPS10 domain-containing receptor 2, a neurotrophin receptor in the sortilin family that is most highly expressed in the nervous system. It plays a role in neurotrophic factor signaling, and its expression can be influenced by stress hormones.

Is rs11731003 linked to alcohol withdrawal?

A genome-wide association study found this variant was significantly associated with the number of alcohol withdrawal symptoms in European-American adults (p = 4.3 x 10^-9, n = 1,478). The genome-wide significant signal was not observed in an African-American cohort of 1,231 individuals.

Does rs11731003 affect SORCS2 gene expression?

GTEx data from 953 donors show this variant is associated with increased SORCS2 expression in esophageal muscularis tissue. Separately, lab experiments found that SORCS2 expression rises in human neural cells during ethanol exposure and withdrawal.

Why do stress hormones matter for the SORCS2 variant?

The risk haplotype is predicted to disrupt a regulatory element modulated by stress hormones, with tissue-specific activity in the human hippocampus. Laboratory experiments in human neural lineage cells confirmed that changing stress hormone levels alters SORCS2 expression.

Does this variant have the same effect across different ancestries?

Based on current evidence, the genome-wide significant association was found only in European-American participants. No genome-wide significant results were observed in 1,231 African-American individuals, and it is currently unclear whether this reflects a true biological difference or a difference in statistical power.