GeneticsTier 2Medical Sciences concept

Complex/polygenic disease genetics - GWAS, twin studies, gene-environment interaction (HLA-B27/ERAP1, NOD2)

Core concept

Complex disease = many common variants of small effect + environment, not one causative mutation
- Common disease-common variant model; typical GWAS OR 1.1-1.3 per allele
- Contrast Mendelian disease: rare variant, large effect, high penetrance
GWAS - hundreds of thousands of SNPs across thousands of cases and controls
- Genome-wide significance p < 5 x 10^-8 (Bonferroni for ~1 million independent tests)
- The hit is a tag SNP in linkage disequilibrium with the causal variant, and ~90% of hits are non-coding/regulatory - it names a locus, not a gene
- Requires large samples, replication cohorts, and correction for population stratification (principal components)
Polygenic risk score - weighted sum of risk alleles; discriminates at population level, poor at the individual level, and derived mostly in European cohorts so transports poorly across ancestries

Twin and family studies

```

Heritability (h2) ~ 2 x (concordance MZ - concordance DZ) [Falconer]

```

MZ share 100%, DZ share 50% of segregating variation, both share the family environment
- MZ concordance well below 100% = the environmental contribution (T1DM ~30-50%, MS ~25-30%, SLE ~25%, RA ~15%)
lambda-s = risk to a sib / population risk - a family-clustering measure (AS lambda-s ~80, very high)
Missing heritability - GWAS hits explain only a fraction of twin-derived h2; explained by rare variants, epistasis, structural variation, gene-environment interaction and overestimated h2

Worked examples

Disease	Genetics	Environment
Ankylosing spondylitis	HLA-B27 (~90% of patients but only ~5% of B27+ develop it); ERAP1 only in B27-positive individuals - the textbook epistasis	Gut microbiome, subclinical ileal inflammation
Crohn's disease	NOD2/CARD15 (bacterial muramyl dipeptide sensing) - ileal, stricturing, early-onset; ATG16L1, IL23R (protective variant)	Smoking (harmful in Crohn's, protective in UC), microbiome
T1DM	HLA-DR3/DR4-DQ2/DQ8 ~50% of genetic risk; INS, PTPN22, CTLA4	Enterovirus, early-life exposures
Coeliac	HLA-DQ2/DQ8 necessary but not sufficient (~30% of the population carry it)	Gluten - a necessary environmental trigger

ERAP1 x HLA-B27 and HLA-DQ2 x gluten are the two cleanest gene-environment / gene-gene interactions in the syllabus

A GWAS-derived risk allele is not a diagnostic test. HLA-B27 in a patient with back pain shifts probability; it does not diagnose
High negative predictive value is where HLA typing earns its place: HLA-DQ2/DQ8 negative essentially excludes coeliac disease
GWAS loci have delivered drug targets - IL23R -> ustekinumab/risankizumab, IL-6 -> tocilizumab, PCSK9, HMGCR (statins); a target with human genetic support is roughly twice as likely to succeed in trials
Mendelian randomisation uses these variants as instruments to test causality from observational data (LDL and Lp(a) causal; HDL and CRP not)
Family history remains a better clinical predictor than a polygenic risk score for most conditions

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.