Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Abstract

Schizophrenia (SCZ) is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits with heritability estimated at up to 80%1,2. We adopted two analytic approaches to determine the extent to which common genetic variation underlies risk of SCZ using genome-wide association study (GWAS) data from 3,322 European individuals with SCZ and 3,587 controls. First, we implicate the major histocompatibility complex (MHC). Second, we provide molecular genetic evidence for a substantial polygenic component to risk of SCZ involving thousands of common alleles of very small effect. We show that this component also contributes to risk of bipolar disorder (BPD), but not to multiple non-psychiatric diseases.

Assessment of first and second degree relatives of individuals with bipolar disorder shows increased genetic risk scores in both affected relatives and young At‐Risk Individuals

“…Many genomic variants together contribute to overall risk (termed polygenic risk) for a number of complex traits [Peterson et al, 2011; Hamshere et al, 2013; Meyers et al, 2013], and this genetic architecture is evident in a number of psychiatric conditions—including BP [Purcell et al, 2009; Lee et al, 2012, 2013; Smoller et al, 2013; Bramon et al, 2014]. While the elucidation of the genetic causes for BP has been challenging, the field is progressing in understanding the genetic architecture of this complex disorder (reviewed in [Craddock and Sklar, 2013]) and in identifying specific genes which increase risk [Sklar et al, 2011].…”

“…While the elucidation of the genetic causes for BP has been challenging, the field is progressing in understanding the genetic architecture of this complex disorder (reviewed in [Craddock and Sklar, 2013]) and in identifying specific genes which increase risk [Sklar et al, 2011]. Polygenic risk scores based on multiple genetic variants across the genome [Purcell et al, 2009] have successfully discriminated between groups of unrelated cases and controls [Patel et al, 2010] and also individuals with BP broadly defined as schizoaffective or non‐schizoaffective [Hamshere et al, 2011], indicating the potential utility of risk score analysis in clinical diagnoses at a population level. However, it is unclear as to whether polygenic risk score analysis, with or without other clinical or biomarker data, could be useful for diagnosis or risk prediction in persons with a significant family history of BP, particularly given the non‐random inheritance of population risk alleles in related individuals and confounding shared environmental effects within a family.…”

“…It is now understood that multiple genes containing both common and rare variants contribute to the genetic architecture of BP [Sullivan et al, 2012], and there are significant overlaps in the single nucleotide polymorphism (SNP)‐based heritabilities of BP with both schizophrenia and major depression [Lee et al, 2013]. Indeed, variation across many thousands of common risk variants together (termed polygenic risk [Purcell et al, 2009]) contributes a substantial proportion (i.e., 25–40%) of the percentage of phenotypic variance at a population level [Lee et al, 2011; 2013]—although most of those loci do not individually reach genome‐wide significance thresholds for disease association with current sample sizes [Craddock and Sklar, 2013; Dudbridge, 2013]. …”

“…Examination of the cumulative effects of inheriting multiple risk alleles—each of which are significantly or nominally associated with disease risk—has been able to powerfully differentiate groups of cases from controls in independent population‐based studies [Purcell et al, 2014, 2009; Patel et al, 2010; Ayalew et al, 2012; Terwisscha van Scheltinga et al, 2012]. However, despite phenotypic aggregation within families [McGuffin et al, 2003; Lichtenstein et al, 2009], no studies have so far examined polygenic risk incorporating these common genetic factors in a family context in adults, with only one group to date reporting on polygenic risk in adolescent offspring of individuals with BP [Whalley et al, 2012, 2013].…”

Shared genetic contribution to ischemic stroke and Alzheimer's disease

“…More than 20 variants have now been identified that contribute to AD,20, 21, 22 and in IS recent progress has resulted in the identification of a number of variants, the majority of which have been associated with specific stroke subtypes 23, 24, 25, 26, 27, 28. Indeed, recent evidence from GWAS indicates that a large proportion of risk in complex diseases such as AD and IS is attributable to the combined effects of a large number of common genetic variants,29, 30 each conferring only a small amount of disease risk 31, 32, 33. Recent studies estimate the proportion of variance explained by the genetic contribution from common variants to AD and IS to be approximately 24.0% and 18.0%, respectively.…”