Dataset Information

Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype-Based Approach.

ABSTRACT: Risk profile scores (RPS) derived from genome-wide association studies (GWAS) explain a considerable amount of susceptibility for schizophrenia (SCZ). However, little is known about how common genetic risk factors for SCZ influence the structure and function of the human brain, largely due to the constraints of imaging sample sizes. In the current study, we use a novel recall-by-genotype (RbG) methodological approach, where we sample young adults from a population cohort (Avon Longitudinal Study of Parents and Children: N genotyped = 8365) based on their SCZ-RPS. We compared 197 healthy individuals at extremes of low (N = 99) or high (N = 98) SCZ-RPS with behavioral tests, and structural and functional magnetic resonance imaging (fMRI). We first provide methodological details that will inform the design of future RbG studies for common SCZ genetic risk. We further provide an between group analysis of the RbG individuals (low vs high SCZ-RPS) who underwent structural neuroimaging data (T1-weighted scans) and fMRI data during a reversal learning task. While we found little evidence for morphometric differences between the low and high SCZ-RPS groups, we observed an impact of SCZ-RPS on blood oxygen level-dependent (BOLD) signal during reward processing in the ventral striatum (PFWE-VS-CORRECTED = .037), a previously investigated broader reward-related network (PFWE-ROIS-CORRECTED = .008), and across the whole brain (PFWE-WHOLE-BRAIN-CORRECTED = .013). We also describe the study strategy and discuss specific challenges of RbG for SCZ risk (such as SCZ-RPS related homoscedasticity). This study will help to elucidate the behavioral and imaging phenotypes that are associated with SCZ genetic risk.

SUBMITTER: Lancaster TM

PROVIDER: S-EPMC6403064 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype-Based Approach.

Lancaster Thomas M TM Dimitriadis Stavros L SL Tansey Katherine E KE Perry Gavin G Ihssen Niklas N Jones Derek K DK Singh Krish D KD Holmans Peter P Pocklington Andrew A Davey Smith George G Zammit Stan S Hall Jeremy J O'Donovan Michael C MC Owen Michael J MJ Linden David E DE

Schizophrenia bulletin 20190301 2

Risk profile scores (RPS) derived from genome-wide association studies (GWAS) explain a considerable amount of susceptibility for schizophrenia (SCZ). However, little is known about how common genetic risk factors for SCZ influence the structure and function of the human brain, largely due to the constraints of imaging sample sizes. In the current study, we use a novel recall-by-genotype (RbG) methodological approach, where we sample young adults from a population cohort (Avon Longitudinal Study ...[more]

PMID: 29608775

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Project description:Recently, 125 loci with genome-wide support for association with schizophrenia were identified. We investigated the impact of these variants and their accumulated genetic risk on brain activation in five neurocognitive domains of the Research Domain Criteria (working memory, reward processing, episodic memory, social cognition and emotion processing). In 578 healthy subjects we tested for association (i) of a polygenic risk profile score (RPS) including all single-nucleotide polymorphisms (SNPs) reaching genome-wide significance in the recent genome-wide association studies (GWAS) meta-analysis and (ii) of all independent genome-wide significant loci separately that showed sufficient distribution of all allelic groups in our sample (105 SNPs). The RPS was nominally associated with perigenual anterior cingulate and posterior cingulate/precuneus activation during episodic memory (PFWE(ROI)=0.047) and social cognition (PFWE(ROI)=0.025), respectively. Single SNP analyses revealed that rs9607782, located near EP300, was significantly associated with amygdala recruitment during emotion processing (PFWE(ROI)=1.63 × 10-4, surpassing Bonferroni correction for the number of SNPs). Importantly, this association was replicable in an independent sample (N=150; PFWE(ROI)<0.025). Other SNP effects previously associated with imaging phenotypes were nominally significant, but did not withstand correction for the number of SNPs tested. To assess whether there was true signal within our data, we repeated single SNP analyses with 105 randomly chosen non-schizophrenia-associated variants, observing fewer significant results and lower association probabilities. Applying stringent methodological procedures, we found preliminary evidence for the notion that genetic risk for schizophrenia conferred by rs9607782 may be mediated by amygdala function. We critically evaluate the potential caveats of the methodological approaches employed and offer suggestions for future studies.

Project description:BackgroundSchizophrenia is a heritable psychiatric disorder with a polygenic architecture. Genome-wide association studies have reported that an increasing number of risk-associated variants and polygenic risk scores (PRSs) explain 17% of the variance in the disorder. Substantial heterogeneity exists in the effect of these variants, and aggregating them based on biologically relevant functions may provide mechanistic insight into the disorder.MethodsUsing the largest schizophrenia genome-wide association study conducted to date, we associated PRSs based on 5 gene sets previously found to contribute to schizophrenia pathophysiology-postsynaptic density of excitatory synapses, postsynaptic membrane, dendritic spine, axon, and histone H3-K4 methylation-along with respective whole-genome PRSs, with neuroimaging (n > 29,000) and reported psychotic-like experiences (n > 119,000) variables in healthy UK Biobank subjects.ResultsSeveral variables were significantly associated with the axon gene-set (psychotic-like communications, parahippocampal gyrus volume, fractional anisotropy thalamic radiations, and fractional anisotropy posterior thalamic radiations (β range -0.016 to 0.0916, false discovery rate-corrected p [pFDR] ≤ .05), postsynaptic density gene-set (psychotic-like experiences distress, global surface area, and cingulate lobe surface area [β range -0.014 to 0.0588, pFDR ≤ .05]), and histone gene set (entorhinal surface area: β = -0.016, pFDR = .035). From these, whole-genome PRSs were significantly associated with psychotic-like communications (β = 0.2218, pFDR = 1.34 × 10-7), distress (β = 0.1943, pFDR = 7.28 × 10-16), and fractional anisotropy thalamic radiations (β = -0.0143, pFDR = .036). Permutation analysis revealed that these associations were not due to chance.ConclusionsOur results indicate that genetic variation in 3 gene sets relevant to schizophrenia may confer risk for the disorder through effects on previously implicated neuroimaging variables. Because associations were stronger overall for whole-genome PRSs, findings here highlight that selection of biologically relevant variants is not yet sufficient to address the heterogeneity of the disorder.

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Dataset Information

Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype-Based Approach.

Publications

Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype-Based Approach.

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