Grama, Steluta, Willcocks, Isabella ORCID: https://orcid.org/0000-0002-3568-5236, Hubert, John, Pardiñas, Antonio ORCID: https://orcid.org/0000-0001-6845-7590, Legge, Sophie, Bracher-Smith, Matthew, Menzies, Georgina ORCID: https://orcid.org/0000-0002-6600-6507, Hall, Lynsey, Pocklington, Andrew ORCID: https://orcid.org/0000-0002-2137-0452, Anney, Richard ORCID: https://orcid.org/0000-0002-6083-407X, Bray, Nicholas ORCID: https://orcid.org/0000-0002-4357-574X, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483 and Caseras, Xavier ORCID: https://orcid.org/0000-0002-8490-6891 2020. Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort. Translational Psychiatry 10 , 309. 10.1038/s41398-020-00940-0 |
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Abstract
Research has shown differences in subcortical brain volumes between participants with schizophrenia and healthy controls. However, none of these differences have been found to associate with schizophrenia polygenic risk. Here, in a large sample (n = 14,701) of unaffected participants from the UK Biobank, we test whether schizophrenia polygenic risk scores (PRS) limited to specific gene-sets predict subcortical brain volumes. We compare associations with schizophrenia PRS at the whole genome level (‘genomic’, including all SNPs associated with the disorder at a p-value threshold < 0.05) with ‘genic’ PRS (based on SNPs in the vicinity of known genes), ‘intergenic’ PRS (based on the remaining SNPs), and genic PRS limited to SNPs within 7 gene-sets previously found to be enriched for genetic association with schizophrenia (‘abnormal behaviour,’ ‘abnormal long-term potentiation,’ ‘abnormal nervous system electrophysiology,’ ‘FMRP targets,’ ‘5HT2C channels,’ ‘CaV2 channels’ and ‘loss-of-function intolerant genes’). We observe a negative association between the ‘abnormal behaviour’ gene-set PRS and volume of the right thalamus that survived correction for multiple testing (ß = −0.031, pFDR = 0.005) and was robust to different schizophrenia PRS p-value thresholds. In contrast, the only association with genomic PRS surviving correction for multiple testing was for right pallidum, which was observed using a schizophrenia PRS p-value threshold < 0.01 (ß = −0.032, p = 0.0003, pFDR = 0.02), but not when using other PRS P-value thresholds. We conclude that schizophrenia PRS limited to functional gene sets may provide a better means of capturing differences in subcortical brain volume than whole genome PRS approaches.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Advanced Research Computing @ Cardiff (ARCCA) Biosciences MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Cardiff University Brain Research Imaging Centre (CUBRIC) Medicine |
Publisher: | Springer Nature |
ISSN: | 2158-3188 |
Funders: | MRC |
Date of First Compliant Deposit: | 21 July 2020 |
Date of Acceptance: | 14 July 2020 |
Last Modified: | 25 Jul 2024 16:11 |
URI: | https://orca.cardiff.ac.uk/id/eprint/133569 |
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