Benjamin I Perry, Nicholas Bowker, Stephen Burgess, Nicholas J Wareham, Rachel Upthegrove, Peter B Jones, Claudia Langenberg, Golam M Khandaker
{"title":"精神分裂症、心脏代谢和炎症相关特征之间共享遗传病因学的证据：遗传相关性和共定位分析。","authors":"Benjamin I Perry, Nicholas Bowker, Stephen Burgess, Nicholas J Wareham, Rachel Upthegrove, Peter B Jones, Claudia Langenberg, Golam M Khandaker","doi":"10.1093/schizbullopen/sgac001","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology.</p><p><strong>Methods: </strong>We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology.</p><p><strong>Results: </strong>We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (r<sub>g</sub> = -0.07; 95% C.I., -0.03,0.12; <i>P</i> = .002) and BMI (r<sub>g</sub> = -0.09; 95% C.I., -0.06, -0.12; <i>P</i> = 1.83 × 10<sup>-5</sup>). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (<i>BDNF</i>); rs8192675 (<i>SLC2A2</i>); rs3800229 (<i>FOXO3</i>); rs17514846 (<i>FURIN</i>)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways.</p><p><strong>Conclusions: </strong>LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders.</p>","PeriodicalId":21348,"journal":{"name":"Schizophrenia Bulletin Open","volume":"3 1","pages":"sgac001"},"PeriodicalIF":0.0000,"publicationDate":"2022-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827407/pdf/","citationCount":"0","resultStr":"{\"title\":\"Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses.\",\"authors\":\"Benjamin I Perry, Nicholas Bowker, Stephen Burgess, Nicholas J Wareham, Rachel Upthegrove, Peter B Jones, Claudia Langenberg, Golam M Khandaker\",\"doi\":\"10.1093/schizbullopen/sgac001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology.</p><p><strong>Methods: </strong>We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology.</p><p><strong>Results: </strong>We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (r<sub>g</sub> = -0.07; 95% C.I., -0.03,0.12; <i>P</i> = .002) and BMI (r<sub>g</sub> = -0.09; 95% C.I., -0.06, -0.12; <i>P</i> = 1.83 × 10<sup>-5</sup>). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (<i>BDNF</i>); rs8192675 (<i>SLC2A2</i>); rs3800229 (<i>FOXO3</i>); rs17514846 (<i>FURIN</i>)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways.</p><p><strong>Conclusions: </strong>LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders.</p>\",\"PeriodicalId\":21348,\"journal\":{\"name\":\"Schizophrenia Bulletin Open\",\"volume\":\"3 1\",\"pages\":\"sgac001\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-01-11\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8827407/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Schizophrenia Bulletin Open\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/schizbullopen/sgac001\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Schizophrenia Bulletin Open","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/schizbullopen/sgac001","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses.
Background: Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology.
Methods: We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology.
Results: We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (rg = -0.07; 95% C.I., -0.03,0.12; P = .002) and BMI (rg = -0.09; 95% C.I., -0.06, -0.12; P = 1.83 × 10-5). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (BDNF); rs8192675 (SLC2A2); rs3800229 (FOXO3); rs17514846 (FURIN)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways.
Conclusions: LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders.
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