Genetics / disease association · BEGINNER LESSON
Risk locus
A risk locus is a fixed position in the genome where variation is associated with increased disease or trait risk. In genome-wide association studies (GWAS), it usually means the lead single-nucleotide polymorphism (SNP) and nearby SNPs in linkage disequilibrium with it.
What it is
A risk locus is not the disease itself and not automatically the causal change. It is a genomic location that shows a statistical association with disease or another trait. In GWAS, a locus is often the top SNP and other nearby SNPs that are correlated with it through linkage disequilibrium, meaning variants tend to be inherited together. Source material also notes that for complex diseases, the associated effect of one variant is often small, so many loci may each contribute a little to overall risk. [0,2]
[1] Prediction of individual genetic risk to disease from genome-wide ... [3] Interpretation of risk loci from genome-wide association ... - PMC
How researchers find and interpret it
Researchers detect risk loci using family linkage studies for Mendelian diseases or GWAS for complex diseases, with different statistical thresholds in each setting. A signal can point to a region rather than a single causal variant because tagging SNPs are chosen based on linkage disequilibrium and may not be the true causal change. Nearby-gene assignment can also mislead: the nearest gene is not always the relevant gene, and only about a third of trait-associated genes are the nearest gene in one Alzheimer’s disease review. [1,2]
[2] functional analysis of cancer predisposition loci - PMC [3] Interpretation of risk loci from genome-wide association ... - PMC
How a risk locus may act
Many disease-associated variants, especially in cancer predisposition, are found in non-protein-coding regions. These regions often affect transcriptional regulation, which means they can change how much RNA transcript is produced from a gene. Expression quantitative trait loci, or eQTLs, are variants associated with transcript levels, so they help prioritize candidate genes for a non-protein-coding risk locus. A positive eQTL result is considered evidence for follow-up, but it can still be confounded by other changes in the tissue being studied. [1]
Limitations and uncertainty
A risk locus gives probability, not destiny. Even when known genetic risk is present, whether a person develops disease can still depend on known and unknown environmental factors. Many loci have modest effects, and the causal variant or gene may remain unknown because molecular follow-up is difficult, time-consuming, and sometimes limited by the lack of a clear genetic code in non-protein-coding DNA. GWAS can also miss very rare variants if they are not well tagged by the tested SNPs. [0,1]
[1] Prediction of individual genetic risk to disease from genome-wide ... [2] functional analysis of cancer predisposition loci - PMC
SEE THE IDEA
From association signal to biological interpretation
A top SNP shows association in GWAS.
Nearby variants in linkage disequilibrium travel with the signal.
The nearest gene is checked, but it may be wrong.
eQTL or other studies ask whether gene activity changes.
A risk locus starts as an association signal, then investigators try to narrow the linked region and test which gene or regulatory change could explain it.
The locus is a starting point for interpretation, not proof of the causal variant or gene.
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Sources and further reading
This general lesson was generated from public source material. It explains a concept; it does not interpret a private paper or provide medical advice.