Ferdinand van ’t Hooft Cardiovascular Genetics and Genomics Group Karolinska Institutet, Stockholm, Sweden Genome-Wide Association Study GWAS

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 disorders Association 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