Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders

Seenae Eum, S. Kristian Hill, Ney Alliey-Rodriguez, James M. Stevenson, Leah H. Rubin, Adam M. Lee, Lauren J. Mills, James L. Reilly, Rebekka Lencer, Sarah K. Keedy, Elena Ivleva, Richard S.E. Keefe, Godfrey D. Pearlson, Brett A. Clementz, Carol A. Tamminga, Matcheri S. Keshavan, Elliot S. Gershon, John A. Sweeney, Jeffrey R. Bishop

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Identifying genetic contributors to cognitive impairments in psychosis-spectrum disorders can advance understanding of disease pathophysiology. Although CNS medications are known to affect cognitive performance, they are often not accounted for in genetic association studies. In this study, we performed a genome-wide association study (GWAS) of global cognitive performance, measured as composite z-scores from the Brief Assessment of Cognition in Schizophrenia (BACS), in persons with psychotic disorders and controls (N = 817; 682 cases and 135 controls) from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Analyses accounting for anticholinergic exposures from both psychiatric and non-psychiatric medications revealed five significantly associated variants located at the chromosome 3p21.1 locus, with the top SNP rs1076425 in the inter-alpha-trypsin inhibitor heavy chain 1 (ITIH1) gene (P = 3.25×E−9). The inclusion of anticholinergic burden improved association models (P < 0.001) and the number of significant SNPs identified. The effect sizes and direction of effect of the top variants remained consistent when investigating findings within individuals receiving specific antipsychotic drugs and after accounting for antipsychotic dose. These associations were replicated in a separate study sample of untreated first-episode psychosis. The chromosome 3p21.1 locus was previously reported to have association with the risk for psychotic disorders and cognitive performance in healthy individuals. Our findings suggest that this region may be a psychosis risk locus that is associated with cognitive mechanisms. Our data highlight the general point that the inclusion of medication exposure information may improve the detection of gene-cognition associations in psychiatric genetic research.

Original languageEnglish (US)
Pages (from-to)1802-1810
Number of pages9
Issue number10
StatePublished - Sep 2021

Bibliographical note

Funding Information:
This work was supported by funding from the National Institute of Mental Health (MH083888 to J.R.B., MH072767 to S.K.H., MH083126 to J.L.R., MH077945 to G.D.P., MH085485 to B.A.C., MH077851 to C.A.T., MH078113 to M.S.K., MH077852 to G.K.T., MH096957 to E.S.G., MH077862 to J.A.S.). J.L.R. has received investigator-initiated support from Naurex, Inc. R.L. has received honoraria, served as a consultant, or advisory board member for Janssen-Cilag, Otsuka Pharma and Lundbeck. R.S.E.K. is the owner of VeraSci, a for-profit business that receives revenues from over 100 companies, most of which are pharmaceutical companies. VeraSci holds the copyright for the BACS used in this study, and R.S.E.K receives royalties directly. He has also received consulting income from Akili in the past year. C.A.T. declares an ad hoc consulting relationship with Sunovion, Astellas and Merck and membership on a Merck DSMB; C.A.T. is on the Clinical Advisory Board at Kynexis and Karuna Therapeutics and holds stock in Karuna. M.S.K. has received support from Sunovion and is a consultant to Forum Pharmaceuticals. J.A.S. has received support from VeraSci. The other authors report nothing to disclose. The funding agencies had no role in the design and conduct of the study collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.


Dive into the research topics of 'Genome-wide association study accounting for anticholinergic burden to examine cognitive dysfunction in psychotic disorders'. Together they form a unique fingerprint.

Cite this