Cindy Boer

General Introduction | 19 1.1 ▲ Figure 4: Allele frequency and osteoarthritis disease risk. Early onset osteoarthritis or Mendelian/ monogenetic forms of osteoarthritis, are caused by single gene mutations. Such genetic variants have large effects, but are rare in the population. Known genes with rare mutations that give rise to early onset osteoarthritis are given in the box. For late onset or the common form of osteoarthritis, many variants and genes confer risk. Meaning that almost all of these variants must have small to moderate effect sizes. Thus common variants with large effect sizes are unlikely to exist for common diseases, al- though it is possible. In the box known GWAS identified loci associated with osteoarthritis are given. Figure adapted from [34, 42] utilizes the LD between SNVs by only measuring the genotype of “tagging” SNVs, SNVs which “tag” the genotype of their LD block ( Figure 5 ), resulting that only several hun- dreds of thousands SNV are needed to efficiently “tag” the full variation across the en- tire genome. Although imputation methods thus provide a cheap method for identifying the full genomic variation, the quality and accuracy of the imputation is dependent on the quality of the reference information. The SNV linkage blocks (haplotypes) needed for imputation are based on reference haplotypes generated via whole genome sequencing in populations. The first efforts to create the human “haplotype-map” was done by the HapMap consortium, in 2005, with the last of the data published in 2009[35, 43]. This first haplotype map was based on the whole genome sequencing data of 692 individuals from 11 global populations[43]. Different haplotypes occur with different frequencies in different populations, some might even be population specific. Thus, more whole ge- nome sequences across multiple population are needed to improve the human haplo- type map, and thereby the quality and accuracy of imputation. This was done in the fol- lowing 1000 Genomes project, which contained 1,092 whole genome sequences from