[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Epidemiology](https://durgical.com/en/epidemiology/) › [Study designs](https://durgical.com/en/epidemiology/areas/designs/) › Linkage and genetic association studies (GWAS)

# Linkage and genetic association studies (GWAS)

- Study design

They look for the region or variant of the genome that travels with a disease: in families (linkage) or comparing cases and controls (association).

Updated Nov 13, 2026

## Key points

- Linkage: in families; measures whether a marker and the disease are inherited together; a LOD score ≥ 3 (odds of 1,000 to 1) suggests linkage.
- Association: unrelated cases and controls; compares allele or genotype frequencies (OR).
- GWAS: hypothesis-free; usual threshold p

On this page

- The basics Key points
- What it is
- How it is built
- Worked example
- Linkage, candidate gene and GWAS
- Markers
- When to use it
- Common pitfalls
- Memory aid
- Elsewhere in DurgiPedia

- Study Test yourself

- Connections Connections

## What it is

Linkage studies follow, in families with several affected members, which genetic markers are inherited together with the disease; they work best for genes of large effect. Association studies compare the frequency of variants between unrelated cases and controls: first with candidate genes chosen by hypothesis, and today with genome-wide association studies (GWAS), which test hundreds of thousands to millions of single nucleotide polymorphisms (SNPs). Because so many tests are run, they need a very strict significance threshold and replication.

## How it is built

- Cases and controls are genotyped on a SNP chip; genotyping quality is checked.
- Stratification (ancestry) is corrected with principal components or controls from the same population.
- Each SNP is tested separately; results are shown in a Manhattan plot.
- Findings are confirmed in an independent replication sample.

## Worked example

- GWAS with 2,000 cases and 2,000 controls (4,000 alleles per group). 1,000,000 SNPs are tested.
- SNP X: risk allele in 1,200 case alleles (30%) and 1,000 control alleles (25%).
- Allelic OR = (1,200 × 3,000) / (2,800 × 1,000) = 1.29.
- Chi-square ≈ 25.1, with p ≈ 5.5 × 10⁻⁷: significant for a single test.
- Genome-wide threshold: 0.05 / 1,000,000 = 5 × 10⁻⁸. The p of X is about 11 times larger.
- Reading: X is promising but does not reach genome-wide significance; it needs replication in another sample.

## Linkage, candidate gene and GWAS

| Approach | Who | What it detects best | Main limitation |
| --- | --- | --- | --- |
| Linkage | Families with several affected members | Rare genes of large effect | Broad regions; little power in complex diseases |
| Candidate gene | Cases and controls | Variants in genes chosen by hypothesis | Many findings did not replicate |
| GWAS | Thousands of cases and controls | Common variants of small effect | Multiple comparisons; marker variant, not the causal one |

## Markers

- GWAS
- SNP
- LOD
- 5 × 10⁻⁸

## When to use it

- They have found regions associated with type 2 diabetes, macular degeneration, autoimmune diseases and many cancers.
- Combining many variants gives polygenic risk scores, whose clinical usefulness is still limited.

## Common pitfalls

- Using p

## Memory aid

Ask the genome a million questions and you need a very loud yes: five with seven zeros in front.

## Test yourself

Think of the answer, then tap the question to see it.

## Why is the GWAS threshold 5 × 10⁻⁸?

It is the Bonferroni adjustment of 0.05 for about one million independent tests: 0.05 / 1,000,000.

## What is population stratification?

Differences in ancestry between cases and controls that create false associations between a SNP and the disease.

## Risk allele in 30% of case alleles and 25% of control alleles. Allelic OR?

(0.30/0.70) / (0.25/0.75) = 0.429 / 0.333 ≈ 1.29.

## How does linkage differ from association?

Linkage studies joint inheritance of marker and disease within families; association compares frequencies in unrelated cases and controls.

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## Elsewhere in DurgiPedia

- [DNA polymorphisms, linkage and DNA fingerprinting](https://durgical.com/en/biochemistry/topics/dna-polymorphisms-linkage-and-dna-fingerprinting/)
- [Genetic tests: what each one finds](https://durgical.com/en/biochemistry/topics/genetic-tests-what-each-one-finds/)

## Connections

## Related 6

- [Family, twin and adoption studies](https://durgical.com/en/epidemiology/family-twin-and-adoption-studies/)
- [Gene-environment interaction](https://durgical.com/en/epidemiology/gene-environment-interaction/)
- [Case-control study](https://durgical.com/en/epidemiology/case-control-study/)
- [Multiple comparisons](https://durgical.com/en/epidemiology/multiple-comparisons/)
- [Odds ratio](https://durgical.com/en/epidemiology/odds-ratio/)
- [Confounding](https://durgical.com/en/epidemiology/confounding/)

[← All of epidemiology](https://durgical.com/en/epidemiology/)

Educational content on epidemiological and statistical methods; the examples use made-up numbers to teach the calculation. Not a clinical or legal guide: current Colombian rules are in the official sources.

Sources: [Genome-Wide Association Studies Fact Sheet](https://www.genome.gov/about-genomics/fact-sheets/Genome-Wide-Association-Studies-Fact-Sheet) (National Human Genome Research Institute, 2020); [Genetic Epidemiology](https://archive.cdc.gov/www_cdc_gov/genomics/resources/books/genepi2.htm) (Centers for Disease Control and Prevention, 1997); [Bonferroni's method](https://www.itl.nist.gov/div898/handbook/prc/section4/prc473.htm) (NIST/SEMATECH e-Handbook of Statistical Methods, National Institute of Standards and Technology, 2012).

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Representative model, for educational purposes only.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/epidemiology/linkage-and-genetic-association-studies/