Ferdinand van ’t HooftCardiovascular Genetics and Genomics Group

Karolinska Institutet, Stockholm, Sweden

Genome-Wide Association Study

GWAS

http://en.wikipedia.org/wiki/Genome-wide_association_study

Human Genome

Genetic variation

Single Nucleotide polymorphism (SNP)

Allele

- One of two copies of a genetic sequence at a chromosomal

location

- Alleles can be considered according to their frequencies in the

human population:

- Common variants – minor allele frequency (MAF) >5%

- Low frequency variants – MAF 0.5-5%

- Rare variants – MAF <0.5%

-Other terms:

- Polymorphism – MAF>1%

- Mutation – MAF<1%

Linkage disequilibrium

Selections of SNPs representative for LD-blocks in the genome

Linkage study versus association study

Linkage study of a familial hypercholesterolemia (FH) family

Identification of mutations in PCSK9 as a cause of FH

Linkage study - analysis of monogenic disordersAssociation study - analysis of complex disorders/phenotype- association between specific genetic variation and disease

Genome-Wide Association Study

GWAS of seven common diseases

Replication and Meta-analysis

Genetic loci identified with GWAS – March 2010

Alternative applications GWAS: quantitative parameters

Close-up of relationship with LDL-C in LDLR region

Example of a locus with a secondary joint association signal conditioning on a primary signal

Mapping of the 19p12 genetic locus identified by GWAS of plasma TG concentration

Identification of TM6SF2 as putative functional gene/protein in the

chromosome 19p12 locus associated with plasma TG

concentration