Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study

Abstract

A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10-8). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS.

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Acknowledgements

This work was supported by the Swedish Research Council (Vetenskapsrådet, award D0886501 to PFS). The Sweden Schizophrenia Study was supported by NIMH R01 MH077139. KK received funding from the European Union’s Horizon 2020 Research and Innovation programme under the Marie Skłodowska-Curie grant agreement (No. 793530) and from the Government of Canada Banting Postdoctoral Fellowship Programme.

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Correspondence to Patrick F. Sullivan.

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PFS reports the following potential competing financial interests: Current: Lundbeck (advisory committee, grant recipient); Past 3 years: Pfizer (scientific advisory board), Element Genomics (consultation fee), and Roche (speaker reimbursement). HL has served as a speaker for Evolan Pharma and Shire, and has received research grants from Shire; all outside the submitted work. All other authors report no disclosures related to this work.

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Kowalec, K., Lu, Y., Sariaslan, A. et al. Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0575-1

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