So far, research in this area has applied PRS optimised to account for the presence of SZ in the population, but this should not necessarily be optimal to account for brain variability.
It is possible that only a subset of SZ associated variants would relate to the size of subcortical structures 16, and even then not all subcortical volumes would necessarily associate to the same subset of variants. Identifying brain intermediate phenotypes is key for our understanding of the mechanisms behind SZ, unveiling its etiopathogenesis and ultimately developing more effective clinical interventions.Īn alternative explanation for the lack of association could be the potential heterogeneity in the effect of risk alleles across the brain. However, previous research has also shown similar subcortical abnormalities in unaffected relatives of SZ patients 11, 12, 13, 14 and in healthy carriers of rare alleles penetrant for SZ 15, 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. This could suggest that these differences in subcortical volumes are a consequence, as opposed to a premorbid risk marker, of schizophrenia albeit other interpretations are also plausible, for example that these are driven by environmental risk. Although recent large multicentric studies have consistently shown differences in subcortical brain volumes between SZ participants and healthy controls 5, 6, research looking at the combined risk effect of common alleles using polygenic risk scores (PRS) 7 has shown no association between PRS for SZ and subcortical volumes 8, 9, 10. Despite the increase in our understanding of the genetic factors related to SZ, our knowledge about its neurobiological underpinnings remains scarce. The most recent published Genome Wide Association Study (GWAS) identified 145 independent loci associated with SZ at genome-wide significance 4. Recent advances in our understanding of the genetic risk for SZ have confirmed its polygenic nature, with hundreds-if not thousands 2-of common risk alleles explaining ~25% of the variance in liability to the disorder 3. Schizophrenia (SZ) is a highly heritable (h 2 ~ 80%) 1 psychiatric disorder that can carry a severe burden for affected individuals and their families.
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. 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, p FDR = 0.02), but not when using other PRS P-value thresholds. 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, p FDR = 0.005) and was robust to different schizophrenia PRS p-value thresholds. 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’). 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. However, none of these differences have been found to associate with schizophrenia polygenic risk. Research has shown differences in subcortical brain volumes between participants with schizophrenia and healthy controls.
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