Correlations between relatives: From Mendelian theory to complete genome sequence.

It is 100 years since R. A. Fisher proposed that a Mendelian model of genetic variant effects, additive over loci, could explain the patterns of observed phenotypic correlations between relatives. His loci were hypothetical and his model theoretical. It is only about 50 years since the first genetic markers allowed the detection of even variants with major effects on phenotype, and only 20 years since the development of single-nucleotide polymorphism technology provided dense markers over the genome. Then both mappings in defined pedigrees and population-based genome-wide association studies samples allowed the detection of multiple contributing variants of smaller effect. Finally, with methods based on genotypic correlations between individuals, or on allelic associations between loci, the additive heritability contributions of the genome can be estimated from large population samples. In this review we trace, from 1918 to 2018, the analysis of observed phenotypic correlations between relatives to estimate underlying genetic components of traits in human populations. As with studies from 1918 onward, we use height as the example trait where not only data are readily available, but where Fisher's model of large numbers of variants of infinitesimal effect appears to provide a good approximation to reality. However, we also trace the use of phenotypic and genotypic correlations between relatives in mapping causal variants and resolving genetic contributions to more complex human traits. With the availability of DNA sequence data, we can hope to not only estimate the total genetic contribution to a trait, but to resolve effects of individual genetic variants on biological function.