Polygenic risk for schizophrenia and subcortical brain anatomy in the UK Biobank cohort

Steluta Grama,Andrew J Pocklington,Valentina Escott-Price,Nicholas J Bray,Georgina E Menzies,Isabella Willcocks,Lynsey S Hall,Sophie E Legge,Matthew Bracher-Smith,Xavier Caseras,Antonio F Pardiñas,John J Hubert,Richard J L Anney

doi:10.1038/s41398-020-00940-0

Steluta Grama, Andrew J Pocklington + Show 11 more

Open Access

https://doi.org/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.

Highlights

Schizophrenia (SZ) is a highly heritable (h2 ~ 80%)[1] psychiatric disorder that can carry a severe burden for affected individuals and their families
Significant associations after False Discovery Rate (FDR) correction (14 tests for genomic polygenic risk scores (PRS), 28 for genic/intergenic PRS, 98 for gene-set PRS) are highlighted with an asterisk. 5HT2C: 5-HT2C receptor complex genes set; abnormal_beh: abnormal behaviour genes set; abnormal_ltp: abnormal long term potentiation genes set; abnormal_nse: abnormal nervous system electrophysiology; CaV2 channels: voltagegated calcium channel complexes genes set; FMRP targets: targets of fragile X mental retardation protein genes set; LoF intolerant: loss of function intolerant genes set. In this proof-of-concept study we revisited the association between polygenic risk for SZ and subcortical volumes using the largest and most powered Genome Wide Association Study (GWAS) published to date[4] in a uniquely large sample of unaffected participants, examining the effect of restricting common allele risk to gene sets known to be enriched for SZ4,21
Our results showed that schizophrenia polygenic risk restricted to certain gene sets predicted more variance of neuroimaging biomarkers than an overall genomic approach

Summary

Introduction

Schizophrenia (SZ) is a highly heritable (h2 ~ 80%)[1] psychiatric disorder that can carry a severe burden for affected individuals and their families. Recent advances in our understanding of the genetic risk for SZ have confirmed its polygenic nature, with hundreds—if not thousands2—of common risk alleles explaining ~25% of the variance in liability to the disorder[3]. The most recent published Genome Wide Association Study (GWAS) identified 145 independent loci associated with SZ at. Grama et al Translational Psychiatry (2020)10:309 in unaffected relatives of SZ patients[11,12,13,14] and in healthy carriers of rare alleles penetrant for SZ15, suggesting that at least some of these subcortical differences could well represent intermediate phenotypes for SZ that lie on the causal pathway between genetic variation and expression of the disorder. Examples of that are recent studies attempting to identify ‘core gene-sets’ that make a larger contribution to SZ risk[17], or to predict brain anatomy[18] and functional connectivity[19] via PRS limited to genes up- or down-regulated by MIR13720

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