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[Preprint]. 2024 Apr 16:2024.04.16.24305885.
doi: 10.1101/2024.04.16.24305885.

Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics

Upasana Bhattacharyya  1   2 , Jibin John  1   2 , Todd Lencz  1   2   3 , Max Lam  1   4   5
Affiliations

Dissecting Schizophrenia Biology Using Pleiotropy with Cognitive Genomics

Upasana Bhattacharyya et al. medRxiv. .

Abstract

Given the increasingly large number of loci discovered by psychiatric GWAS, specification of the key biological pathways underlying these loci has become a priority for the field. We have previously leveraged the pleiotropic genetic relationships between schizophrenia and two cognitive phenotypes (educational attainment and cognitive task performance) to differentiate two subsets of illness-relevant SNPs: (1) those with "concordant" alleles, which are associated with reduced cognitive ability/education and increased schizophrenia risk; and (2) those with "discordant" alleles linked to reduced educational and/or cognitive levels but lower schizophrenia susceptibility. In the present study, we extend our prior work, utilizing larger input GWAS datasets and a more powerful statistical approach to pleiotropic meta-analysis, the Pleiotropic Locus Exploration and Interpretation using Optimal test (PLEIO). Our pleiotropic meta-analysis of schizophrenia and the two cognitive phenotypes revealed 768 significant loci (159 novel). Among these, 347 loci harbored concordant SNPs, 270 encompassed discordant SNPs, and 151 "dual" loci contained concordant and discordant SNPs. Competitive gene-set analysis using MAGMA related concordant SNP loci with neurodevelopmental pathways (e.g., neurogenesis), whereas discordant loci were associated with mature neuronal synaptic functions. These distinctions were also observed in BrainSpan analysis of temporal enrichment patterns across developmental periods, with concordant loci containing more prenatally expressed genes than discordant loci. Dual loci were enriched for genes related to mRNA translation initiation, representing a novel finding in the schizophrenia literature.

Keywords: GWAS; cognition; educational attainment; pleiotropy; schizophrenia.

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Conflict of interest statement

Competing interests The authors declare no competing interests.

Figures

Figure 1.
Figure 1.
Study strategy and workflow Methods underlying the present report are broken down into (i) GWAS summary statistics QC phase using ‘mungesumstats,’ (ii) PLEIO pleiotropy meta-analysis, (iii) FUMA GWAS annotation and (iv) MAGMA gene set analysis and further downstream analytic procedures.
Figure 2:
Figure 2:
Miami plot of PLEIO meta-analysis results Top panel: visualization of variant subsets derived from –blup recalibrated effect size directions: (i) Concordant variants (red) (ii) Discordant variants (green) and (iii) Dual variants (blue). Bottom pane : Complete pleiotropic meta-analysis results from the PLEIO tool, NPR: novel loci (orange), Not Previously Reported; Novel index variants reaching genome-wide significance 5×10−8 are represented as black dots.
Figure 3:
Figure 3:
Venn Diagram Comparing Significant PLEIO Loci to Significant Loci from Input GWASs Pleio_meta: results from PLEIO meta-analysis; SCZ_PGC3: Schizophrenia GWAS input (PGC Schizophrenia Working Group); Edu_Lee: Education GWAS; CTP_Lam: Cognitive task performance GWAS.
Figure 4.
Figure 4.
Brainspan Temporal Gene Expression Profiles Top panel: Brainspan gene expression profiles for ‘Concordant’ genes. Middle panel: Brainspan gene expression profiles for ‘Discordant’ genes. Bottom panel: Brainspan gene expression profiles for ‘Dual’ genes. x-axis: Development time in Weeks. y-axis: standardized (z-scores) of normalized gene expression values in BrainSpan.
See this image and copyright information in PMC

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References

    1. Charlson F.J., Ferrari A.J., Santomauro D.F., Diminic S., Stockings E., Scott J.G., McGrath J.J., and Whiteford H.A. (2018). Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. Schizophr. Bull. 44, 1195–1203. - PMC - PubMed
    1. Trubetskoy V., Pardiñas A.F., Qi T., Panagiotaropoulou G., Awasthi S., Bigdeli T.B., Bryois J., Chen C.-Y., Dennison C.A., Hall L.S., et al. (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature 604, 502–508. - PMC - PubMed
    1. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014). Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427. - PMC - PubMed
    1. Pardiñas A.F., Holmans P., Pocklington A.J., Escott-Price V., Ripke S., Carrera N., Legge S.E., Bishop S., Cameron D., Hamshere M.L., et al. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nat. Genet. 50, 381–389. - PMC - PubMed
    1. Ripke S., O’Dushlaine C., Chambert K., Moran J.L., Kähler A.K., Akterin S., Bergen S.E., Collins A.L., Crowley J.J., Fromer M., et al. (2013). Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45, 1150–1159. - PMC - PubMed

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