QTL Mapping in Humans Lon Cardon Stacey Cherny

QTL Mapping in Humans Lon Cardon, Stacey Cherny University of Oxford Goncalo Abecasis University of Michigan Pak Sham Institute of Psychiatry, King’s College, London

3 Stages of Genetic Mapping • Are there genes influencing this trait? – Epidemiological studies • Where are those genes? – Linkage analysis • What are those genes? – Association analysis

3 Stages of Genetic Mapping • Are there genes influencing this trait? – Epidemiological studies • Where are those genes? – Linkage analysis • What are those genes? – Association analysis

Polygenic Traits 1 Gene 2 Genes 3 Genes 4 Genes 3 Genotypes 3 Phenotypes 9 Genotypes 5 Phenotypes 27 Genotypes 7 Phenotypes 81 Genotypes 9 Phenotypes QTL mapping: identify specific loci SEM work this week

QTL Linkage Analysis • Aim: Identify regions of genome that contain (‘are linked with’) gene(s) influencing trait • Follows directly from biometrical model – Builds on all concepts developed this week – Twins informative, as are extended sibships larger kindreds • Only one new data type added to design: genotypes – ‘identity by descent’ derived from genotypes

r. MZ = r. DZ = 1 r. MZ = 1, r. DZ = 0. 5 E e E ^ r. MZ = 1, r. DZ = C c C A a Twin 1 trait A Q Q q q a Twin 2 trait c e

Some QTL linkage analysis software programs • ACT: Chris Amos’ variance components suite • Genehunter: Leonid Kruglyak’s discrete-trait package, extended to simple VC • SOLAR: John Blangero’s variance components package • QTDT/Merlin: Goncalo Abecasis’ association/linkage VC program and likelihood engine • Many others, large and small • Mx: Mike Neale’s variance components program

Friday afternoon schedule • 1: 30 -2: 30: Linkage analysis theory: Abecasis/Sham • 2: 30 -3: 00: QTL linkage analysis in Mx: Cardon/Cherny • 3: 00 -3: 30: Tea • 3: 30 -4: 00: Multivariate QTL linkage analysis: Cardon/Cherny • 4: 00 -4: 45: Beyond linkage: some current issues in QTL identification (aka: gratuitous promotion of advanced workshop): Cardon