Exploring the unknown assumptions about allelic architecture and strategies for susceptibility variant discovery.docVIP

Minireview Exploring the unknown: assumptions about allelic architecture and strategies for susceptibility variant discovery Mark I McCarthy Addresses: Oxford Centre for Diabetes, Endocrinology Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK, and the Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX7 7BN, UK. Email: mark.mccarthy@drl.ox.ac.uk who feel a continued search for common susceptibility variants is of limited value, because all that remains to be found are variants of vanishingly small effect [8], and those Abstract Identification of common-variant associations for many common disorders has been highly effective, but the loci detected so far typically explain only a small proportion of the genetic pre- disposition to disease. Extending explained genetic variance is one of the major near-term goals of human genetic research. Next-generation sequencing technologies offer great promise, but optimal strategies for their deployment remain uncertain, not least because we lack a clear view of the characteristics of the variants being sought. Here, I discuss what can and cannot be inferred about complex trait disease architecture from the information currently available and review the implications for future research strategies. who feel that, pending reductions in costs that will allow high-quality, whole-genome sequence data to be generated in adequately powered sample sizes, there is virtue in persisting with an approach of proven worth [9]. There is good reason to assume that this ‘dark matter’ is neither an illusion created by inflated estimates of herita- bility nor the consequence of marked non-additivity of effects [10,11]. If so, then the sum total of genetic variance should largely be explicable in terms of the main effects of all the risk alleles of various typ