How disease genes are found: linkage, association and sequencing
Three strategies find the genes behind diseases: tracking markers through families, comparing many patients with controls, and sequencing every gene.
Key facts
- Linkage analysis follows markers through families with a Mendelian disorder; markers near the disease gene travel with it because recombination rarely separates them.
- The LOD score is the base-10 logarithm of the odds of linkage versus no linkage; 3 or more (1000 to 1) is accepted as evidence of linkage.
- Linkage and positional cloning found genes such as CFTR (1989) and HTT (1993).
- Genome-wide association studies compare hundreds of thousands of variants in cases and controls; a genome-wide significance threshold of about 5 × 10⁻⁸ corrects for the many tests.
- Exome and genome sequencing, especially of a child and both parents, now find most new Mendelian disease genes.
In detail
- Association signals mark a region; because nearby variants are inherited together (linkage disequilibrium), the causal gene still has to be identified.
- In consanguineous families, long stretches of homozygosity point to the region of a recessive gene.
- International matchmaking platforms connect patients with variants in the same candidate gene, which provides the independent cases needed to prove a new gene.
- Proof that a gene causes disease comes from several unrelated patients, segregation in families and functional studies in cells or animal models.
- In children with suspected genetic disorders, exome sequencing gives a diagnosis in roughly a quarter to two-fifths of cases.
- Also called
- Linkage analysis and LOD score, Genome-wide association and exome sequencing
Clinical notes
- A negative exome can become positive on reanalysis a year or two later, as new genes are discovered.
Test yourself
Think of the answer, then tap the question to see it.
What does a LOD score of 3 mean?
The odds favour linkage over no linkage by 1000 to 1, the usual threshold for accepting linkage.
Why does a genome-wide association signal not identify the causal gene directly?
Nearby variants are inherited together (linkage disequilibrium), so the signal marks a region that may contain several genes.
Why sequence both parents together with an affected child?
It shows which variants are new in the child (de novo) and how inherited variants are shared, which sharply narrows the candidates.
Connections
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Genome-Wide Association Studies (GWAS) (National Human Genome Research Institute (NHGRI), 2026); What are genome-wide association studies?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Exome (National Human Genome Research Institute (NHGRI), 2026); Bioinformatics (National Human Genome Research Institute (NHGRI), 2026).
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Representative model, for educational purposes only.