Etiology of Schizophrenia: Strong Association With Certain Rare Copy Number Variants

Genetics research
Genetics research
Genetic risk from rare copy number variants and common single-nucleotide polymorphisms may contribute to liability to schizophrenia.

Genetic data from patients with schizophrenia suggest an additive model in which the presence of a rare copy number variant (CNV) requires little added contribution from common single-nucleotide polymorphisms to produce schizophrenia, according to study results published in the American Journal of Psychiatry.

Investigators abstracted genetic data from 21,094 case participants with schizophrenia and 20,227 control participants from the Psychiatric Genomics Consortium. CNV data were derived from genomewide association study arrays and processed by the Psychiatric Genomics Consortium CNV analysis group. Three CNV risk classifications were described: CNVs previously associated with schizophrenia, CNVs with large deletions (≥500 kb), and total CNV burden. Mean polygenic risk scores (PRSs) were generated for each study participant on the basis of the presence and respective weights of single-nucleotide polymorphisms. Mean PRSs were compared between study participants with and without rare CNVs. Logistic regression was performed to model the joint effects of PRS and CNVs on schizophrenia liability.

Among case participants with schizophrenia, the mean PRS for CNV carriers was significantly lower compared with that for noncarriers (P =.03), a trend that strengthened with increasing risk from the specific CNVs. When CNVs were stratified on the basis of the odds ratio (OR) of their association with schizophrenia, only carriers of CNVs with the greatest OR values (>15) had a significantly lower PRS1 score than noncarriers. For control participants, however, carriers of CNVs with larger effect sizes (odds ratios >15) had significantly higher mean risk scores than CNVs with smaller effect sizes. An increase in total CNV burden was associated with significantly decreased PRS1 in case participants (P =.0024), but not control participants. Among noncarriers of schizophrenia-associated CNVs, large deletions and total CNV burden were associated with lower PRS1, suggesting an additive model. Case participants with 22q11.2 deletions had much lower PRS1 scores compared with noncarrier case participants. As such, individuals with the 22q11.2 deletion require little added polygenic risk to develop schizophrenia.

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These data provide insight into the “genetic architecture” of schizophrenia, investigators wrote, by elucidating the precise influence of genetic risk factor on liability to schizophrenia. Further research is necessarily to enhance scientific understanding of the etiology of schizophrenia.


Bergen SE, Ploner A, Howrigan D, et al. Joint contributions of rare copy number variants and common SNPs to risk for schizophrenia [published online November 5, 2018]. Am J Psychiatry. doi: 10.1176/appi.ajp.2018.17040467