Rare and non-additive sources of genetic variation in human disease

This project will seek to identify sources of genetic variation that are complementary to the common additive variants currently being identified by large-scale Genome-Wide Association Meta Analyses (GWAMA). Initially, we will investigate the role of intra-locus interactions (dominance) in the normal variation of complex traits. It has been estimated that dominance accounts for up to 20% of the total genetic variance of many complex traits1, but very few specific examples of non-additive alleles have so far been identified1. Partly, this is because the contribution of any recessive variant to the phenotypic variance is expected to be small, especially if that variant is rare2. Previous work has shown that the aggregate of all non-additive effects, as determined by the inbreeding load, has a detrimental effect on stature and cognition in humans3. We will extend this work to quantify the inbreeding load on 41 quantitative traits, including many traits of medical importance.
Subsequently, we will seek to identify specific genomic loci at which regional homozygosity influences any of these 41 complex traits. Making use of such regional mapping, we will also prioritize the search for recessive haplotypes in cases of microcephalic dwarfism currently lacking a molecular diagnosis.
Finally, we will use recently gathered whole genome sequence data, from the historically isolated populations of Orkney and Shetland, to search for rare variants of large additive effect. Variants that are globally rare may reach appreciable frequency in small isolated populations, due to genetic drift and/or founder effects. These cohorts have been deeply phenotyped, increasing the opportunities to identify novel associations.

References
1) Zhu Z, et al. (2015) Dominance genetic variation contributes little to the missing heritability for human complex traits. Am J Hum Genet. 2015 Mar 5;96(3):377-85
2) Hill WG, Goddard ME, Visscher PM (2008) Data and Theory Point to Mainly Additive Genetic Variance for Complex Traits. PLoS Genet 4(2): e1000008. doi:10.1371/journal.pgen.1000008
3) Joshi P.K, et al. (2015) Directional dominance on stature and cognition in diverse human populations. Nature. 2015 Jul 23;523(7561):459-62