QTL Mapping in Humans Lon Cardon, Stacey Cherny Goncalo Abecasis 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 2 Genes  9 Genotypes  5 Phenotypes 3 Genes  27 Genotypes  7 Phenotypes 4 Genes  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

E E C C A A Q Q rMZ = rDZ = 1 rMZ = 1, rDZ = 0.5 ^ rMZ = 1, rDZ =  e Twin 1 trait Twin 2 trait

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