Classification of genetic variants by composition. Schematic of sequence and structural variants compared to reference sequence. Sequence variation (indicated by red line) refers to single-nucleotide variants and small (less than 1 kb) indels. Structural variation includes inversions, translocations and copy-number variants, which result in the presence of a segment of DNA in variable numbers compared to the reference sequence, as in duplications, deletions or insertions. Adapted from [4].

The allelic spectrum of disease is dependent on the number of genetic variants, their frequency in a population and on the size of their phenotypic effect. Family-based linkage studies have proved successful in identifying causative genetic variants in rare Mendelian disorders, which are, by definition, caused by highly penetrant variants that have a low frequency in the population. Complex diseases are caused by multiple genetic variants that confer incremental risk of disease. Genome-wide association studies have sufficient power to detect genetic variants with modest phenotypic effects, provided that they occur at a high frequency in the population. Adapted from [92].

Identification of genetic variation underlying human disease using linkage analysis and genome-wide association studies. (a) Rare Mendelian traits, such as a monogenic disease with autosomal dominance inheritance, can be studied using linkage analysis in a family. The disease status is followed within a pedigree (seven affected individuals depicted in red). (b) The disease loci (red bar) co-segregates with the genetic marker (blue bar), located 10 centimorgans (cM) apart. Each of the seven individuals with the disease carries the blue genetic marker, both inherited from the affected 'parent' chromosome (yellow). (c) Genetic variants underlying common diseases can be statistically identified by using SNP-based linkage disequilibrium (LD) maps. The frequency of a causative variant (red diamond) will be higher (62%) among those with the disease when compared with a control population (50%). (d) LD map of 11 variants cluster into three blocks of correlation r² > 0.8 (red scale correlation matrix). The LD between polymorphisms needs to be empirically determined by genotyping a population and calculating the correlation.