Positional Cloning Genetics Chromosome Region Association Study LOD

Positional Cloning Genetics Chromosome Region Association Study LOD Sib pairs Genomics Physical Mapping/ Sequencing Candidate Gene Selection/ Polymorphism Detection Mutation Characterization/ Functional Annotation

Netherton Syndrome Linkage Chavanas et al. , Am J Hum Genet, 66: 914 -921, 2000

Netherton Syndrome Haplotypes Chavanas et al. , Am J Hum Genet, 66: 914 -921, 2000

Chavanas et al. 2000, Nature Genetics

Inflammatory Bowel Disease Genome Screen Hampe et al. , Am J Hum Genet, 64: 808 -816, 1999

Inflammatory Bowel Disease Genome Screen Hampe et al. , Am J Hum Genet, 64: 808 -816, 1999

Allelic Association A Special Type of Linkage 3/5 3/6 2/6 5/6 3/5 3/2 2/6 5/2 Both families are ‘linked’ with the marker, but a different allele is involved. This is Linkage but no Association

Allelic Association A Special Type of Linkage 3/5 3/6 2/6 5/6 3/2 2/4 6/2 4/6 6/6 All families are ‘linked’ with the marker Allele 6 is ‘associated’ with disease Linkage is just association within families 2/6 6/6

Allelic Association A Special Type of Linkage Controls Cases 6/6 6/2 3/5 3/4 3/6 2/4 3/2 5/6 3/6 4/6 6/6 2/6 5/2 Allele 6 is ‘associated’ with disease 2/6

Association study: Uses Pharmacogenetics genotyping clinically relevant samples (toxicity vs efficacy) Insurance purposes contentious, but likely at some point Candidate genes for specific diseases common practice in medicine/genetics Positional cloning the most frequent source of new loci at present Genome-wide association with 2 -3 million SNPs, can search whole genome exhaustively