Expressive

rs11994760 (NEFL): Tobacco and Alcohol Use Variant

Key takeaways

  • rs11994760 sits in the NEFM-NEFL region, which encodes neurofilament proteins - the structural scaffolding inside nerve cells
  • This locus was identified in a multi-ancestry genome-wide study of tobacco and alcohol use covering more than 3.4 million participants
  • GTEx data shows the alternate allele reduces neurofilament gene expression in the cerebellum and reward-related brain regions, while increasing it in whole blood
  • Variant-specific effect sizes are not reported in the available study text, so the individual contribution of this locus to substance use traits is not quantifiable from current evidence

Key takeaways

  • rs11994760 sits in the NEFM-NEFL region (encoding neurofilament medium and light chain proteins, which form the structural internal scaffolding of nerve cells)
  • This locus was identified in a multi-ancestry genome-wide study of tobacco and alcohol use behaviors covering more than 3.4 million participants
  • GTEx data shows the alternate allele reduces expression of neurofilament genes in the cerebellum and reward-related brain regions, while increasing NEFL expression in whole blood
  • Variant-specific effect sizes are not reported in the available study text, so the individual contribution of this locus to substance use traits cannot be quantified from current evidence

What the research says

A multi-ancestry genome-wide association study (GWAS - a scan of the entire genome for variants statistically linked to a trait) of 3.4 million individuals, approximately 21% of non-European ancestry, identified 2,143 associated loci and 3,823 independently associated variants across five tobacco and alcohol phenotypes: smoking initiation (n = 3,383,199), age at first regular smoking (n = 728,826), cigarettes per day (n = 784,353), smoking cessation (n = 1,400,535), and drinks per week (n = 2,965,643), with this locus among the identified regions. Separate GTEx expression data (from 953 donors) shows that the alternate allele at rs11994760 is linked to reduced NEFL expression in the cerebellar hemisphere and cerebellum, and to increased NEFL expression in whole blood - opposite directions in brain versus blood GTEx Portal.

Reported associations

  • Tobacco use behaviors: This locus was implicated in a large multi-ancestry GWAS covering smoking initiation, cigarettes per day, smoking cessation, and age at first regular smoking, across up to 3.4 million participants; variant-specific effect sizes for rs11994760 are not available in the provided study text
  • Alcohol consumption: The same study examined drinks per week (n = 2,965,643) as a co-analyzed phenotype; variant-specific effect sizes are not available
  • NEFL expression in cerebellum and cerebellar hemisphere: The alternate allele is associated with reduced NEFL expression in both regions GTEx Portal
  • NEFL expression in whole blood: The alternate allele is associated with increased NEFL expression in whole blood, the opposite direction from the brain tissue findings GTEx Portal
  • ENSG00000272157 expression in brain: The alternate allele is associated with reduced expression of this nearby gene in the cerebellum, cerebellar hemisphere, and nucleus accumbens basal ganglia GTEx Portal
  • ENSG00000301773 expression in brain: The alternate allele is associated with reduced expression of this nearby gene in the nucleus accumbens basal ganglia and caudate basal ganglia GTEx Portal

Evidence quality

The tobacco and alcohol GWAS is among the largest genomic analyses of substance use behaviors to date, with over 3.4 million participants across 60 contributing cohorts and a stringent discovery threshold of P < 5 x 10^-9. Most identified variants showed consistent effect sizes across ancestry groups, and a cross-validation approach confirmed that the vast majority of sentinel variants had high posterior probabilities of replication. However, the available study text does not report variant-level statistics for rs11994760 specifically, so the individual effect size and exact significance level for this locus cannot be stated from current evidence. The study authors note that polygenic risk scores built in one ancestry group perform poorly in others, a limitation that applies across all identified loci. GTEx eQTL evidence comes from 953 donors with FDR-controlled thresholds, providing reliable direction-of-effect data for the expression associations reported above.

Tissue-specific expression effects

  • NEFL: Reduced expression in the cerebellar hemisphere and cerebellum; increased expression in whole blood - the direction of effect is tissue-dependent GTEx Portal
  • ENSG00000272157 (a gene at this locus): Reduced expression in the cerebellum, cerebellar hemisphere, and nucleus accumbens basal ganglia (a region involved in reward and motivation processing) GTEx Portal
  • ENSG00000301773 (another nearby gene): Reduced expression in the nucleus accumbens basal ganglia and caudate basal ganglia (both part of the brain's reward and motor control circuitry) GTEx Portal

Lifestyle considerations

No lifestyle considerations on file for this variant.

Lifestyle context

Concrete actions anchored to the cited research. We do not prescribe, we describe.

Discuss with your doctor

  • smoking initiation genetic susceptibility Moderate

    NEFM-NEFL neurofilament variants alter expression in brain reward circuits, increasing smoking initiation susceptibility

    Discuss genetic predisposition and smoking prevention strategies

Frequently asked questions

What do the NEFL and NEFM genes do?

NEFL (neurofilament light chain) and NEFM (neurofilament medium chain) encode proteins that form the structural framework inside nerve cells, similar to scaffolding inside a building. This framework helps maintain neuron shape and size, which influences how electrical signals travel through the nervous system.

Is rs11994760 linked to smoking or drinking behavior?

This variant sits in a region identified in a large multi-ancestry genetic study of tobacco and alcohol use behaviors covering more than 3.4 million participants. The available study text does not report a variant-specific effect size for rs11994760, so the strength of this individual association cannot be quantified from current evidence.

What does it mean that rs11994760 affects brain gene expression?

GTEx data shows the variant is linked to lower levels of NEFL gene activity in the cerebellum and parts of the basal ganglia - brain regions involved in movement coordination and reward processing. This is evidence of a biological mechanism, not a direct measure of brain function or behavioral risk.

Does this variant affect gene expression the same way in all tissues?

No. GTEx data shows the variant reduces NEFL expression in brain regions but increases it in whole blood. This tissue-specific divergence in direction is documented, but its biological significance is not established from the available evidence.

How large was the study that flagged this variant?

The tobacco and alcohol GWAS included over 3.4 million individuals across 60 contributing cohorts, with approximately 21% from non-European ancestries. It is one of the largest genomic studies of substance use behaviors conducted to date.