The role of SLC39A8.p.( Ala391Thr ) in schizophrenia symptom severity and cognitive ability: cross‐sectional studies of schizophrenia and the general UK population

Smart, Sophie E. ORCID: https://orcid.org/0000-0002-6709-5425, Legge, Sophie E., Fenner, Eilidh, Pardiñas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Woolway, Grace, Lynham, Amy J. ORCID: https://orcid.org/0000-0002-3189-6888, Escott‐Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009, Wilkinson, Lawrence ORCID: https://orcid.org/0000-0002-9337-6124, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862 and Walters, James T.R. ORCID: https://orcid.org/0000-0002-6980-4053 2025. The role of SLC39A8.p.( Ala391Thr ) in schizophrenia symptom severity and cognitive ability: cross‐sectional studies of schizophrenia and the general UK population. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics , e33037. 10.1002/ajmg.b.33037

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Abstract

The missense SNP NC_000004.12:g.102267552C>T (also known as SLC39A8.p.(Ala391Thr), rs13107325) in SLC39A8 encodes a zinc transporter. This SNP has been linked to schizophrenia and is the likely causal variant for one of the genome‐wide association loci associated with the disorder. Using regression analyses, we tested whether the schizophrenia‐risk allele at p.(Ala391Thr) was associated with schizophrenia‐related phenotypes, including positive, negative, and disorganized symptoms, cognitive ability, educational attainment, and age of psychosis onset, within three schizophrenia cohorts (combined N = 1232) and, with equivalent phenotypes, in a sample of population controls (UK Biobank, N = 355,069). We also used the population controls to test for associations with rare protein‐truncating and deleterious missense variants within SLC39A8. Within the schizophrenia cohorts, after correction for multiple testing, p.(Ala391Thr) was not significantly associated with any schizophrenia‐related phenotypes. In the unaffected participants from the UK Biobank, the schizophrenia‐risk allele at p.(Ala391Thr) was associated with significantly poorer cognitive ability and fluid intelligence, a lower probability of obtaining GCSEs or a degree‐level qualification, and fewer years in education. There was no association between p.(Ala391Thr) and self‐reported psychotic experiences in this cohort. Rare variants in SLC39A8 were nominally associated with poorer cognitive ability, but these associations did not survive correction for multiple testing. The schizophrenia‐risk allele was associated with poorer cognitive ability, but not psychotic experiences, in a volunteer sample drawn from the general population. We found no evidence that p.(Ala391Thr) was associated with symptom severity in schizophrenia. To understand the impact of rare variants in SLC39A8 on cognitive impairment, larger independent samples are required.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Professional Services > Advanced Research Computing @ Cardiff (ARCCA) Schools > Medicine Schools > Psychology
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Wiley
ISSN:	1552-4841
Date of First Compliant Deposit:	1 July 2025
Date of Acceptance:	29 April 2025
Last Modified:	02 Jul 2025 14:47
URI:	https://orca.cardiff.ac.uk/id/eprint/179438

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