Rare variants in complex traits: novel identification strategies and the role of de novo mutations

Abstract

Following the limited success of linkage and association studies aimed at identifying the genetic causes of common neurodevelopmental syndromes like autism and schizophrenia, complex traits such as these have recently been considered under the 'common disease-rare variant' hypothesis. Prior to this hypothesis, the study of candidate genes has enabled the discovery of rare variants in complex disorders, and in turn some of these variants have highlighted the genetic contribution of de novo variants. De novo variants belong to a subcategory of spontaneous rare variants that are largely associated with sporadic diseases, which include some complex psychiatric disorders where the affected individuals do not transmit the genetic defects they carry because of their reduced reproductive fitness. Interestingly, recent studies have demonstrated the rate of germline de novo mutations to be higher in individuals with complex psychiatric disorders by comparison to what is seen in unaffected control individuals; moreover, de novo mutations carried by affected individuals have generally been more deleterious than those observed in control individuals. Advanced sequencing technologies have recently enabled the undertaking of massive parallel sequencing projects that can cover the entire coding sequences (exome) or genome of several individuals at once. Such advances have thus fostered the emergence of novel genetic hypotheses and ideas to investigate disease-causative genetic variations. The genetic underpinnings of a number of sporadic complex diseases is now becoming partly explained and more major breakthroughs for complex traits genomics should be expected in the near future.