Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci

Smeland, Olav B.; Shadrin, Alexey; Bahrami, Shahram; Broce, Iris; Tesli, Martin; Frei, Oleksandr; Wirgenes, Katrine Verena; O’Connell, Kevin; Krull, Florian; Bettella, Francesco; Steen, Nils Eiel; Sugrue, Leo P.; Wang, Yunpeng; Svenningsson, Per; Sharma, Manu; Pihlstrøm, Lasse; Toft, Mathias; O’Donovan, Michael; Djurovic, Srdjan; Desikan, Rahul S.; Dale, Anders M.; Andreassen, Ole A.

doi:10.1016/j.biopsych.2020.01.026

Cited by 59 publications

(65 citation statements)

References 79 publications

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“…Functional annotation indicated that the shared variants between BIP and CVD are mostly intronic and intergenic, which is in line with other GWAS findings [ 24 , 31 ]. The results indicate the shared SNPs influence gene expression via regulatory effects [ 56 ].…”

Section: Discussionsupporting

confidence: 89%

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Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

et al. 2021

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Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.

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Section: Discussionsupporting

confidence: 89%

“…P -values are corrected for inflation using a genomic inflation control procedure [ 12 , 28 ]. Consistent with previous publications [ 12 , 24 , 31 , 32 ], we used the thresholds condFDR<0.01 and conjFDR<0.05. For further information, see Supplementary Methods and method review [ 28 ].…”

Section: Methodsmentioning

confidence: 99%

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

et al. 2021

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“…SLC39A8 encodes a transmembrane transporter protein for zinc and iron. This genetic variant has been linked to blood pressure 50 , diabetes 51 , Parkinson’s disease 52, 53 , schizophrenia 52, 53 , alcohol consumption 54 , haemoglobin and haematocrit 55 , and brain morphology 6, 56, 57 . Cluster 47 comprises eleven genetic variants related to SLC39A12 ( ZIP12 ).…”

Section: Resultsmentioning

confidence: 99%

“…Mutations in this gene can lead to congenital disorder of glycosylation, a multisystem developmental disorder with intellectual disability (MIM 616721) 47,48 . This genetic variant has been linked to a large number of traits, including those linked to blood pressure 49 , diabetes 50 , Parkinson's disease and schizophrenia 51,52 , alcohol consumption 53 , haemoglobin and haematocrit 54 and brain morphology 36,55,56 . Voxel-wise association map with rs13107325 (SLC39A8) (Fig.…”

Section: Zinc Transportersmentioning

confidence: 99%

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

Wang

Martins-Bach

Alfaro-Almagro

et al. 2021

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A key aim of epidemiological neuroscience studies is the identification of novel markers to assess brain health and evaluate the efficacy of therapeutic interventions. A broad range of tissue constituents associated with healthy brain functions and diseases (e.g., iron, myelin and calcium) are characterised by unique magnetic properties, motivating the development of measurements sensitive to these effects. Quantitative susceptibility mapping (QSM) is an emerging MRI technique which enables in vivo quantification of tissue magnetic susceptibility, providing the opportunity to identify such markers. In this study, we developed a robust QSM modelling pipeline and evaluated the potential of QSM in a cohort of 35,885 subjects (ages 45-82), alongside extensive genetic and phenotypic associations as part of UK Biobank. Our analysis identified a rich set of distinctive phenotypic and genetic associations with QSM. This included phenotypic associations with body iron, diet, alcohol and diseases, and genetic associations related to a broad range of biological functions including iron, calcium homeostasis, myelination, extracellular matrix. Importantly, we found that QSM and T2* have unique patterns of associations, demonstrating the added value in including QSM IDPs in the UK Biobank brain imaging resource, with considerable promise to identify novel in vivo brain health markers.

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“…To verify if PD and alcohol dependence are genetically correlated, we accessed the GWAS catalog (https://www.ebi.ac.uk/gwas/ home), a curated collection of human GWASs. We identified at least two other risk loci, at IGSF9B and SLC39A8, shared by the two conditions (44,(52)(53)(54). More recently, SNPs in LRRK2 were associated with cancer (55,56) and inflammatory conditions (including infectious and autoimmune diseases) (57).…”

Section: Discussionmentioning

confidence: 98%

LRRK2 Gene Variants Associated With a Higher Risk for Alcohol Dependence in Multiethnic Populations

et al. 2021

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Background: Genetics influence the vulnerability to alcohol use disorders, and among the implicated genes, three previous studies have provided evidences for the involvement of LRRK2 in alcohol dependence (AD). LRRK2 expression is broadly dysregulated in postmortem brain from AD humans, as well as in the brain of mice with alcohol dependent-like behaviors and in a zebrafish model of alcohol preference. The aim of the present study was to evaluate the association of variants in the LRRK2 gene with AD in multiethnic populations from South and North America.Methods: Alcohol-screening questionnaires [such as CAGE and Alcohol Use Disorders Identification Test (AUDIT)] were used to determine individual risk of AD. Multivariate logistic regression analyses were done in three independent populations (898 individuals from Bambuí, Brazil; 3,015 individuals from Pelotas, Brazil; and 1,316 from the United States). Linkage disequilibrium and conditional analyses, as well as in silico functional analyses, were also conducted.Results: Four LRRK2 variants were significantly associated with AD in our discovery cohort (Bambuí): rs4768231, rs4767971, rs7307310, and rs1465527. Two of these variants (rs4768231 and rs4767971) were replicated in both Pelotas and US cohorts. The consistent association signal (at the LRRK2 locus) found in populations with different genetic backgrounds reinforces the relevance of our findings.Conclusion: Taken together, these results support the notion that genetic variants in the LRRK2 locus are risk factors for AD in humans.

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Genome-wide Association Analysis of Parkinson’s Disease and Schizophrenia Reveals Shared Genetic Architecture and Identifies Novel Risk Loci

Cited by 59 publications

References 79 publications

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes

Phenotypic and genetic associations of quantitative magnetic susceptibility in UK Biobank brain imaging

LRRK2 Gene Variants Associated With a Higher Risk for Alcohol Dependence in Multiethnic Populations

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