Higher genetic risk of schizophrenia is associated with lower cognitive performance in healthy individuals

Shafee, R.; Nanda, P.; Padmanabhan, J. L.; Tandon, N.; Alliey-Rodriguez, N.; Keefe, R. S. E.; Hill, S. K.; Bishop, J. R.; Clementz, B. A.; Tamminga, C. A.; Gershon, E. S.; Pearlson, G. D.; Keshavan, M. S.; Sweeney, J. A.; Robinson, E. B.; McCarroll, S. A.

doi:10.1101/103622

bioRxiv · 10.1101/103622

Higher genetic risk of schizophrenia is associated with lower cognitive performance in healthy individuals

Shafee, R.·Nanda, P.·Padmanabhan, J. L.·Tandon, N.·Alliey-Rodriguez, N.·Keefe, R. S. E.·Hill, S. K.·Bishop, J. R.·Clementz, B. A.·Tamminga, C. A.·Gershon, E. S.·Pearlson, G. D.·Keshavan, M. S.·Sweeney, J. A.·Robinson, E. B.·McCarroll, S. A.

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Abstract

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of the genetic risk of schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychosis patients; a measure of premorbid intelligence that is minimally affected by psychosis (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide SNP data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was associated with lower BACS scores (r = -0.19, p = 1 x 10-4 at PT = 1 x 10-4) but did not associate with WRAT or EY, suggesting that these areas of cognition vary in their etiologic relationships with schizophrenia. Among individuals with psychosis, PRSSCZ did not associate with variation in cognitive performance. These findings suggest that the same cognitive abilities that are disrupted in psychotic disorders are also associated with schizophrenia genetic risk in the general population. Specific cognitive phenotypes, independent of education or general intelligence, could be more deeply studied for insight into the specific processes affected by the genetic influences on psychosis.\n\nSignificancePsychotic disorders such as schizophrenia often involve profound cognitive deficits, the genetic underpinnings of which remain to be elucidated. Poor educational performance early in life is a well-known risk factor for future psychotic illness, potentially reflecting either shared genetic influences or other risk factors that are epidemiologically correlated. Here we show that, in apparently healthy individuals, common genetic risk factors for schizophrenia associate with lower performance in areas of cognition that are impaired in psychotic disorders but do not associate independently with educational attainment or more general measures of intelligence. These results suggest that specific cognitive phenotypes - independent of education or general intelligence - could be more deeply studied for insight into the processes affected by the genetic influences on psychosis.

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Shafee, R., Nanda, P., Padmanabhan, J. L., Tandon, N., Alliey-Rodriguez, N., Keefe, R. S. E., Hill, S. K., Bishop, J. R., Clementz, B. A., Tamminga, C. A., Gershon, E. S., Pearlson, G. D., Keshavan, M. S., Sweeney, J. A., Robinson, E. B., McCarroll, S. A.. 2017-01-27. Higher genetic risk of schizophrenia is associated with lower cognitive performance in healthy individuals. https://doi.org/10.1101/103622

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