- Chang, Lun-Hsien, Whitfield, John, Liu, Mengzhen, Medland, Sarah, Hickie, Ian, Martin, Nicholas, Verhulst, Brad, Heath, Andrew, Madden, Pamela, Statham, Dixie, Gillespie, Nathan, Gscan Consortium
- Authors: Chang, Lun-Hsien , Whitfield, John , Liu, Mengzhen , Medland, Sarah , Hickie, Ian , Martin, Nicholas , Verhulst, Brad , Heath, Andrew , Madden, Pamela , Statham, Dixie , Gillespie, Nathan , Gscan Consortium
- Date: 2019
- Type: Text , Journal article
- Relation: Drug and Alcohol Dependence Vol. 205, no. (2019), p.
- Full Text: false
- Reviewed:
- Description: Background: Substance use, substance use disorders (SUDs), and psychiatric disorders commonly co-occur. Genetic risk common to these complex traits is an important explanation; however, little is known about how polygenic risk for tobacco or alcohol use overlaps the genetic risk for the comorbid SUDs and psychiatric disorders. Methods: We constructed polygenic risk scores (PRSs) using GWAS meta-analysis summary statistics from a large discovery sample, GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN), for smoking initiation (SI; N = 631,564), age of initiating regular smoking (AI; N = 258,251), cigarettes per day (CPD; N = 258,999), smoking cessation (SC; N = 312,273), and drinks per week (DPW; N = 527,402). We then estimated the fixed effect of these PRSs on the liability to 15 phenotypes related to tobacco and alcohol use, substance use disorders, and psychiatric disorders in an independent target sample of Australian adults. Results: After adjusting for multiple testing, 10 of 75 combinations of discovery and target phenotypes remained significant. PRS-SI (R2 range: 1.98%–5.09 %) was positively associated with SI, DPW, and with DSM-IV and FTND nicotine dependence, and conduct disorder. PRS-AI (R2: 3.91 %) negatively associated with DPW. PRS-CPD (R2: 1.56 %–1.77 %) positively associated with DSM-IV nicotine dependence and conduct disorder. PRS-DPW (R2: 3.39 %–6.26 %) positively associated with only DPW. The variation of DPW was significantly influenced by sex*PRS-SI, sex*PRS-AI and sex*PRS-DPW. Such interaction effect was not detected in the other 14 phenotypes. Conclusions: Polygenic risks associated with tobacco use are also associated with liability to alcohol consumption, nicotine dependence, and conduct disorder. © 2019 Elsevier B.V.
Genetic aetiology of self-harm ideation and behaviour
- Campos, Adrian, Verweij, Karin, Statham, Dixie, Madden, Pamela, Maciejewski, Dominique, Davis, Katrina, John, Ann, Hotopf, Matthew, Heath, Andrew, Martin, Nicholas, Rentería, Miguel
- Authors: Campos, Adrian , Verweij, Karin , Statham, Dixie , Madden, Pamela , Maciejewski, Dominique , Davis, Katrina , John, Ann , Hotopf, Matthew , Heath, Andrew , Martin, Nicholas , Rentería, Miguel
- Date: 2020
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 10, no. 1 (2020), p.
- Full Text:
- Reviewed:
- Description: Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability (hsnp2) estimates were ~10%, and both traits were highly genetically correlated (LDSC rg > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant. © 2020, The Author(s).
- Description: This research was conducted using data from the UK Biobank resource under application number 25331. AC-G is supported by a UQ Research Training Scholarship from The University of Queensland (UQ). MER thanks the support of the NHMRC and Australian Research Council (ARC), and National Health and Medical Research Council (NHMRC) through a Research Fellowship (GNT1102821) and NHMRC Centre for Research Excellence in Suicide Prevention (GNT1042580). This research was made possible thanks to support from the US National Institutes of Health (grants AA013326, AA07535, AA0758O, AA07728, AA10249, AA13320, AA13321, AA14041, AA11998, AA17688, DA00272, DA012854, DA07261, DA018267, DA018660, DA23668 and DA019951); the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 628911 1047956); the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016 and DP0343921).
- Authors: Campos, Adrian , Verweij, Karin , Statham, Dixie , Madden, Pamela , Maciejewski, Dominique , Davis, Katrina , John, Ann , Hotopf, Matthew , Heath, Andrew , Martin, Nicholas , Rentería, Miguel
- Date: 2020
- Type: Text , Journal article
- Relation: Scientific Reports Vol. 10, no. 1 (2020), p.
- Full Text:
- Reviewed:
- Description: Family studies have identified a heritable component to self-harm that is partially independent from comorbid psychiatric disorders. However, the genetic aetiology of broad sense (non-suicidal and suicidal) self-harm has not been characterised on the molecular level. In addition, controversy exists about the degree to which suicidal and non-suicidal self-harm share a common genetic aetiology. In the present study, we conduct genome-wide association studies (GWAS) on lifetime self-harm ideation and self-harm behaviour (i.e. any lifetime self-harm act regardless of suicidal intent) using data from the UK Biobank (n > 156,000). We also perform genome wide gene-based tests and characterize the SNP heritability and genetic correlations between these traits. Finally, we test whether polygenic risk scores (PRS) for self-harm ideation and self-harm behaviour predict suicide attempt, suicide thoughts and non-suicidal self-harm (NSSH) in an independent target sample of 8,703 Australian adults. Our GWAS results identified one genome-wide significant locus associated with each of the two phenotypes. SNP heritability (hsnp2) estimates were ~10%, and both traits were highly genetically correlated (LDSC rg > 0.8). Gene-based tests identified seven genes associated with self-harm ideation and four with self-harm behaviour. Furthermore, in the target sample, PRS for self-harm ideation were significantly associated with suicide thoughts and NSSH, and PRS for self-harm behaviour predicted suicide thoughts and suicide attempt. Follow up regressions identified a shared genetic aetiology between NSSH and suicide thoughts, and between suicide thoughts and suicide attempt. Evidence for shared genetic aetiology between NSSH and suicide attempt was not statistically significant. © 2020, The Author(s).
- Description: This research was conducted using data from the UK Biobank resource under application number 25331. AC-G is supported by a UQ Research Training Scholarship from The University of Queensland (UQ). MER thanks the support of the NHMRC and Australian Research Council (ARC), and National Health and Medical Research Council (NHMRC) through a Research Fellowship (GNT1102821) and NHMRC Centre for Research Excellence in Suicide Prevention (GNT1042580). This research was made possible thanks to support from the US National Institutes of Health (grants AA013326, AA07535, AA0758O, AA07728, AA10249, AA13320, AA13321, AA14041, AA11998, AA17688, DA00272, DA012854, DA07261, DA018267, DA018660, DA23668 and DA019951); the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 628911 1047956); the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016 and DP0343921).
Trans-ethnic kidney function association study reveals putative causal genes and effects on kidney-specific disease aetiologies
- Morris, Andrew, Le, Thu, Wu, Haojia, Akbarov, Artur, van der Most, Peter, Hemani, Gibran, Smith, George, Mahajan, Anubha, Gaulton, Kyle, Nadkarni, Girish, Valladares-Salgado, Adan, Wacher-Rodarte, Niels, Mychaleckyj, Josyf, Dueker, Nicole, Guo, Xiuqing, Hai, Yang, Haessler, Jeffrey, Kamatani, Yoichiro, Stilp, Adrienne, Zhu, Gu, Cook, James, Arnlov, Johan, Blanton, Susan, de Borst, Martin, Bottinger, Erwin, Buchanan, Thomas, Cechova, Sylvia, Charchar, Fadi, Chu, Pei-Lun, Damman, Jeffrey, Eales, James, Gharavi, Ali, Giedraitis, Vilmantas, Heath, Andrew, Ipp, Eli, Kiryluk, Krzysztof, Kramer, Holly, Kubo, Michiaki, Larsson, Anders, Lindgren, Cecilia, Lu, Yingchang, Madden, Pamela, Montgomery, Grant, Papanicolaou, George, Raffel, Leslie, Sacco, Ralph, Sanchez, Elena, Stark, Holger, Sundstrom, Johan, Taylor, Kent, Xiang, Anny, Zivkovic, Aleksandra, Lind, Lars, Ingelsson, Erik, Martin, Nicholas, Whitfield, John, Cai, Jianwen, Laurie, Cathy, Okada, Yukinori, Matsuda, Koichi, Kooperberg, Charles, Chen, Yii-Der, Rundek, Tatjana, Rich, Stephen, Loos, Ruth, Parra, Esteban, Cruz, Miguel, Rotter, Jerome, Snieder, Harold, Tomaszewski, Maciej, Humphreys, Benjamin, Franceschini, Nora
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
- Full Text:
- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
- Authors: Morris, Andrew , Le, Thu , Wu, Haojia , Akbarov, Artur , van der Most, Peter , Hemani, Gibran , Smith, George , Mahajan, Anubha , Gaulton, Kyle , Nadkarni, Girish , Valladares-Salgado, Adan , Wacher-Rodarte, Niels , Mychaleckyj, Josyf , Dueker, Nicole , Guo, Xiuqing , Hai, Yang , Haessler, Jeffrey , Kamatani, Yoichiro , Stilp, Adrienne , Zhu, Gu , Cook, James , Arnlov, Johan , Blanton, Susan , de Borst, Martin , Bottinger, Erwin , Buchanan, Thomas , Cechova, Sylvia , Charchar, Fadi , Chu, Pei-Lun , Damman, Jeffrey , Eales, James , Gharavi, Ali , Giedraitis, Vilmantas , Heath, Andrew , Ipp, Eli , Kiryluk, Krzysztof , Kramer, Holly , Kubo, Michiaki , Larsson, Anders , Lindgren, Cecilia , Lu, Yingchang , Madden, Pamela , Montgomery, Grant , Papanicolaou, George , Raffel, Leslie , Sacco, Ralph , Sanchez, Elena , Stark, Holger , Sundstrom, Johan , Taylor, Kent , Xiang, Anny , Zivkovic, Aleksandra , Lind, Lars , Ingelsson, Erik , Martin, Nicholas , Whitfield, John , Cai, Jianwen , Laurie, Cathy , Okada, Yukinori , Matsuda, Koichi , Kooperberg, Charles , Chen, Yii-Der , Rundek, Tatjana , Rich, Stephen , Loos, Ruth , Parra, Esteban , Cruz, Miguel , Rotter, Jerome , Snieder, Harold , Tomaszewski, Maciej , Humphreys, Benjamin , Franceschini, Nora
- Date: 2019
- Type: Text , Journal article
- Relation: Nature Communications Vol. 10, no. 1 (2019), p. 1-14
- Full Text:
- Reviewed:
- Description: Chronic kidney disease (CKD) affects ~10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assemble genome-wide association studies of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals of diverse ancestry. We identify 127 distinct association signals with homogeneous effects on eGFR across ancestries and enrichment in genomic annotations including kidney-specific histone modifications. Fine-mapping reveals 40 high-confidence variants driving eGFR associations and highlights putative causal genes with cell-type specific expression in glomerulus, and in proximal and distal nephron. Mendelian randomisation supports causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure and hypertension. These results define novel molecular mechanisms and putative causal genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.
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