Narrowing the Boundaries of the Genetic Architecture of Schizophrenia

Abstract

Genetic architecture of a disease comprises the number, frequency, and effect sizes of genetic risk alleles and the way in which they combine together. Before the genomic revolution, the only clue to underlying genetic architecture of schizophrenia came from the recurrence risks to relatives and the segregation patterns within families. From these clues, very simple genetic architectures could be rejected, but many architectures were consistent with the observed family data. The new era of genome-wide association studies can provide further clues to the genetic architecture of schizophrenia. We explore models of genetic architecture by description rather than the mathematics that underpins them. We conclude that the new genome-wide data allow us to narrow the boundaries on the models of genetic architecture that are consistent with the observed data. A genetic architecture of many common variants of moderate (relative risk > approximately 1.2) can be excluded, yet there is evidence that current generation genome-wide chips do tag an important proportion of the genetic variation for schizophrenia and that the underlying causal variants will include common variants of small effect as well as rarer variants of larger effect. Together, these observations imply that the total number of genetic variants is very large—of the order of thousands. The first generation of studies have generated hypotheses that should be testable in the near future and will further narrow the boundaries on genetic architectures that are consistent with empirical data.

De Novo Mutation in Schizophrenia

“…1 Such a view is consistent with population genetic theory and the so-called mixed model of SZ; it has also received compelling support from recent genomic studies. 2 Genomewide association studies have identified a number of risk loci at genome-wide levels of significance as well as evidence for a substantial burden of common risk loci.…”

The genomics of schizophrenia: update and implications

“…Despite significant efforts, there are no compelling examples of deterministic genetic variants acting in a Mendelian fashion as yet. From a statistical perspective, this genetic architecture implies that very large sample sizes are required (i.e., tens of thousands of cases) for any type of association study as well as for genome-wide linkage approaches (86,87).…”

Polymorphism

“…The following data from two schizophrenia studies are reproduced from Mayo (1978) Imai et al 2001). Wray and Visscher (2010) give the best established associations as part of a thoughtful discussion of all of the issues in unravelling the genetical component of schizophrenia causation.…”