Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries

Background: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Methods: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). Results: SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.

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The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

Science Advances ◽

10.1126/sciadv.abb3063 ◽

2020 ◽

Vol 6 (43) ◽

pp. eabb3063

Author(s):

Wei Xu ◽

Si-Da Han ◽

Can Zhang ◽

Jie-Qiong Li ◽

Yan-Jiang Wang ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Genome Wide Association Study ◽

In Vitro Study ◽

Genome Wide ◽

A Genome ◽

Increased Risk ◽

Pathophysiological Role ◽

Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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Genome-wide association study identifies locus at chromosome 2q32.1 associated with syncope and collapse

Cardiovascular Research ◽

10.1093/cvr/cvz106 ◽

2019 ◽

Vol 116 (1) ◽

pp. 138-148 ◽

Cited By ~ 4

Author(s):

Katra Hadji-Turdeghal ◽

Laura Andreasen ◽

Christian M Hagen ◽

Gustav Ahlberg ◽

Jonas Ghouse ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Psychiatric Research ◽

Carrier Status ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Significant Locus

Abstract Aims Syncope is a common condition associated with frequent hospitalization or visits to the emergency department. Family aggregation and twin studies have shown that syncope has a heritable component. We investigated whether common genetic variants predispose to syncope and collapse. Methods and results We used genome-wide association data on syncope on 408 961 individuals with European ancestry from the UK Biobank study. In a replication study, we used the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n = 86 189), to investigate the risk of incident syncope stratified by genotype carrier status. We report on a genome-wide significant locus located on chromosome 2q32.1 [odds ratio = 1.13, 95% confidence interval (CI) 1.10–1.17, P = 5.8 × 10−15], with lead single nucleotide polymorphism rs12465214 in proximity to the gene zinc finger protein 804a (ZNF804A). This association was also shown in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (1.30, 95% CI 1.15–1.46, P = 1.68 × 10−5) of incident syncope. Quantitative polymerase chain reaction analysis showed ZNF804A to be expressed most abundantly in brain tissue. Conclusion We identified a genome-wide significant locus (rs12465214) associated with syncope and collapse. The association was replicated in an independent cohort. This is the first genome-wide association study to associate a locus with syncope and collapse.

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A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25

Nature Genetics ◽

10.1038/ng.664 ◽

2010 ◽

Vol 42 (10) ◽

pp. 902-905 ◽

Cited By ~ 111

Author(s):

Pirro G Hysi ◽

Terri L Young ◽

David A Mackey ◽

Toby Andrew ◽

Alberto Fernández-Medarde ◽

...

Keyword(s):

Association Study ◽

Refractive Error ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Susceptibility Locus ◽

Genome Wide ◽

A Genome

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The long non-coding RNA CASC20 is a susceptibility locus for heterotopic ossification: results of a genome-wide association study

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2018.02.337 ◽

2018 ◽

Vol 26 ◽

pp. S156

Author(s):

K. Hatzikotoulas ◽

M.J. Clark ◽

S.J. Macinnes ◽

E. Zeggini ◽

M.J. Wilkinson

Keyword(s):

Association Study ◽

Heterotopic Ossification ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Susceptibility Locus ◽

Non Coding Rna ◽

Genome Wide ◽

A Genome ◽

Long Non Coding Rna

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A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2019.02.672 ◽

2019 ◽

Vol 27 ◽

pp. S286

Author(s):

H. Takuwa ◽

M. Nakajima ◽

N. Kumahashi ◽

S. Kuwata ◽

S. Ito ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Susceptibility Locus ◽

Genome Wide ◽

A Genome

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A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

Radiotherapy and Oncology ◽

10.1016/j.radonc.2014.02.012 ◽

2014 ◽

Vol 111 (2) ◽

pp. 178-185 ◽

Cited By ~ 92

Author(s):

Gillian C. Barnett ◽

Deborah Thompson ◽

Laura Fachal ◽

Sarah Kerns ◽

Chris Talbot ◽

...

Keyword(s):

Association Study ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Genome Wide ◽

Common Genetic Variants ◽

A Genome ◽

Radiotherapy Toxicity

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A GENOME-WIDE ASSOCIATION STUDY IN PROGRESSIVE SUPRANUCLEAR PALSY

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2015-312379.16 ◽

2015 ◽

Vol 86 (11) ◽

pp. e4.68-e4

Author(s):

Zhongbo Chen ◽

Aleksey Shatunov ◽

Gilbert Bensimon ◽

Christine Payan ◽

Albert Ludolph ◽

...

Keyword(s):

Progressive Supranuclear Palsy ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Chromosome 17 ◽

Gene Variants ◽

Genome Wide ◽

Mapt Gene ◽

Common Genetic Variants ◽

A Genome

BackgroundProgressive supranuclear palsy (PSP) is a debilitating Parkinsonian movement disorder characterised by tau protein burden. We aimed to identify common genetic variants influencing PSP susceptibility through a genome-wide association analysis (GWAS) of a multi-centre European study, Neuroprotection and Natural History in Parkinson's Plus Syndromes (NNIPPS), recruiting clinically well-characterised patients. We combined this with a meta-analysis of previously-identified gene variants.MethodsWe genotyped 275,684 single nucleotide polymorphisms using Illumina microarrays in 212 PSP cases from the UK, Germany and France, and compared these with 4,707 matched controls. GWAS was performed using PLINK. Meta-analysis was performed with METAL. Genome-wide significance was defined as p<5×10^–8.ResultsWe observed multiple associations on chromosome 17 within or close to the MAPT gene, a well-established risk locus for PSP, confirming the sample and method validity. Of nine other previously reported associations, meta-analysis only confirmed that the MOBP variation (rs1768208) modified PSP risk (p=3.29×10^–13).ConclusionIn the GWAS and meta-analysis, we found the chromosome 17 inversion region to be associated with PSP susceptibility. Furthermore, we have shown that MOBP can modify the risk of PSP, possibly through influencing oligodendrocyte tau inclusions. These identified gene variants provide novel insights into the underlying genetics of sporadic PSP.

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