Genome-Wide Association Study and Genetic Correlation Scan Provide Insights into Its Genetic Architecture of Sleep Health Score in the UK Biobank Cohort

Background: Mitral valve prolapse (MVP) is a common cardiac valve disease, which affects 1 in 40 in the general population. Previous genome-wide association study have identified 6 risk loci for MVP. But these loci explained only partially the genetic risk for MVP. We aim to identify additional risk loci for MVP by adding data set from the UK Biobank. Methods: We reanalyzed 1007/479 cases from the MVP-France study, 1469/862 controls from the MVP-Nantes study for reimputation genotypes using HRC and TOPMed panels. We also incorporated 434 MVP cases and 4527 controls from the UK Biobank for discovery analyses. Genetic association was conducted using SNPTEST and meta-analyses using METAL. We used FUMA for post-genome-wide association study annotations and MAGMA for gene-based and gene-set analyses. Results: We found TOPMed imputation to perform better in terms of accuracy in the lower ranges of minor allele frequency below 0.1. Our updated meta-analysis included UK Biobank study for ≈8 million common single-nucleotide polymorphisms (minor allele frequency >0.01) and replicated the association on Chr2 as the top association signal near TNS1 . We identified an additional risk locus on Chr1 ( SYT2 ) and 2 suggestive risk loci on chr8 ( MSRA ) and chr19 ( FBXO46 ), all driven by common variants. Gene-based association using MAGMA revealed 6 risk genes for MVP with pronounced expression levels in cardiovascular tissues, especially the heart and globally part of enriched GO terms related to cardiac development. Conclusions: We report an updated meta-analysis genome-wide association study for MVP using dense imputation coverage and an improved case-control sample. We describe several loci and genes with MVP spanning biological mechanisms highly relevant to MVP, especially during valve and heart development.

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P15 Cervical intraepithelial neoplasia and cervical cancer: a genome wide association study (GWAS) of the UK biobank cohort

10.1136/ijgc-2019-esgo.78 ◽

2019 ◽

Author(s):

S Bowden ◽

I Kalliala ◽

M Wielscher ◽

B Bodinier ◽

J Flanagan ◽

...

Keyword(s):

Cervical Cancer ◽

Association Study ◽

Cervical Intraepithelial Neoplasia ◽

Genome Wide Association Study ◽

Intraepithelial Neoplasia ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

The Uk

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A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

Human Molecular Genetics ◽

10.1093/hmg/ddaa058 ◽

2020 ◽

Vol 29 (8) ◽

pp. 1396-1404 ◽

Cited By ~ 2

Author(s):

Weihua Meng ◽

Brian W Chan ◽

Cameron Harris ◽

Maxim B Freidin ◽

Harry L Hebert ◽

...

Keyword(s):

Association Study ◽

Shoulder Pain ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

Significant Locus ◽

The Uk

Abstract Background Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. Methods A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. Results We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10−11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10−10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10−8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). Conclusions We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

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Genome-wide association study of medication-use and associated disease in the UK Biobank

Nature Communications ◽

10.1038/s41467-019-09572-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 17

Author(s):

Yeda Wu ◽

Enda M. Byrne ◽

Zhili Zheng ◽

Kathryn E. Kemper ◽

Loic Yengo ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Medication Use ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

The Uk

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Genome-wide association study of coronary artery disease among individuals with diabetes: the UK Biobank

Diabetologia ◽

10.1007/s00125-018-4686-z ◽

2018 ◽

Vol 61 (10) ◽

pp. 2174-2179 ◽

Cited By ~ 4

Author(s):

Tove Fall ◽

Stefan Gustafsson ◽

Marju Orho-Melander ◽

Erik Ingelsson

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Association Study ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Genome Wide ◽

Artery Disease ◽

The Uk

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A genome-wide association study finds novel genetic associations with broadly-defined headache in UK Biobank (N = 223,773)

10.1101/217786 ◽

2017 ◽

Author(s):

Weihua Meng ◽

Mark J Adams ◽

Harry L Hebert ◽

Ian J Deary ◽

Andrew M McIntosh ◽

...

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Genome Wide Association ◽

Uk Biobank ◽

Genetic Associations ◽

Psychological Traits ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractHeadache is the most common neurological symptom and a leading cause of years lived with disability. We sought to identify the genetic variants associated with a broadly-defined headache phenotype in 223,773 subjects from the UK Biobank cohort. We defined headache based on a specific question answered by the UK Biobank participants. We performed a genome-wide association study of headache as a single entity, using 74,461 cases and 149,312 controls. We identified 3,343 SNPs which reached the genome-wide significance level of P < 5 × 10−8. The SNPs were located in 28 loci, with the top SNP of rs11172113 in the LRP1 gene having a P value of 4.92 × 10−47. Of the 28 loci, 14 have previously been associated with migraine. Among 14 new loci, rs77804065 with a P value of 5.87 × 10−15 in the LINC02210-CRHR1 gene was the top SNP.Positive relationships (P < 0.001) between multiple brain tissues and genetic associations were identified through tissue expression analysis, whereas no vascular related tissues showed significant relationships. We identified several significant positive genetic correlations between headache and other psychological traits including neuroticism, depressive symptoms, insomnia, and major depressive disorder.Our results suggest that brain function is closely related to broadly-defined headache. In addition, we also found that many psychological traits have genetic correlations with headache.

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Genome-wide association study of breakfast skipping links clock regulation with food timing

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz076 ◽

2019 ◽

Vol 110 (2) ◽

pp. 473-484 ◽

Cited By ~ 9

Author(s):

Hassan S Dashti ◽

Jordi Merino ◽

Jacqueline M Lane ◽

Yanwei Song ◽

Caren E Smith ◽

...

Keyword(s):

Association Study ◽

Genetic Variants ◽

Statistical Power ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Uk Biobank ◽

Breakfast Cereal ◽

Breakfast Skipping ◽

Genome Wide ◽

The Uk

ABSTRACT Background Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. Objectives The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. Methods We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). Results In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). Conclusions Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

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O21: GENOME-WIDE ASSOCIATION STUDY OF VARICOSE VEINS IN 810,625 INDIVIDUALS IDENTIFIES 45 GENETIC RISK LOCI

British Journal of Surgery ◽

10.1093/bjs/znab117.021 ◽

2021 ◽

Vol 108 (Supplement_1) ◽

Author(s):

WUR Ahmed ◽

A Wiberg ◽

M Ng ◽

D Furniss

Keyword(s):

Association Study ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

Varicose Veins ◽

Phenotypic Expression ◽

Cell Activity ◽

Genome Wide Association ◽

Uk Biobank ◽

Genetic Components ◽

Genome Wide

Abstract Introduction Varicose veins (VV) impact a third of the UK adult population; 10% of patients develop lipodermatosclerosis and ulceration. VV often requires surgical management, however, there is a high-risk of recurrence. VV is a complex disease, where genetic and non-genetic components contribute to overall phenotypic expression. The genetic architecture of VV is poorly understood; we aimed to uncover its genetic basis. Method We conducted hitherto the largest genome-wide association study of VV. In stage one, using UK Biobank, we compared 22,473 VV patients and 379,183 controls. In stage two, replication and meta-analysis were performed in an independent cohort of 113,041 VV cases and 295,928 controls from 23&Me (California, USA). In-silico analysis was conducted in FUMA, MAGMA, and XGR. Result 109 genome-wide significant (P≤ 5×10-8) loci were identified in UK Biobank, 45 of which successfully replicated in the 23&Me cohort. Twenty-seven loci have not been previously reported. FUMA positionally-mapped 128 genes at the replicated loci, with 84 having a combined annotation-dependent depletion score (CADD) >12.37, suggesting functional, deleterious variants. MAGMA analysis implicated pathways involved in cardiovascular system development (P=1.57×10-08) and tube morphogenesis (P=9.35×10-08). Furthermore, XGR revealed enriched pathways in downstream signalling in naive CD8+ T cells (P=0.0017), and encoding structural and core extracellular glycoproteins (both P=0.007). Conclusion We identified 45 variants conferring risk of VV, which provide insights into disease biology. Implicated genes are enriched in pathways involved in vascular development, immune cell activity and extracellular matrix function, and provide new targets for therapeutic development. Take-home message Unravelling the genetic architecture of varicose veins may facilitate our understanding of the disease and guide therapeutic approaches.

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A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank

10.1101/2020.01.20.913228 ◽

2020 ◽

Author(s):

Weihua Meng ◽

Brian W Chan ◽

Cameron Harris ◽

Maxim B Freidin ◽

Harry L Hebert ◽

...

Keyword(s):

Association Study ◽

Shoulder Pain ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

Chromosome 17 ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

The Uk

ABSTRACTBackgroundCommon types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203,309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK.MethodsCases in the UK Biobank were determined by a question which asked the participants if they had experienced pain in the neck or shoulder in the previous month influencing daily activities. Controls were the UK Biobank participants who reported no pain anywhere in the last month. A genome-wide association study was performed adjusting for age, sex, BMI and 9 population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication.ResultsWe identified 3 genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among 4 significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). None of the single nucleotide polymorphisms (SNPs) were replicated in the TwinsUK cohort (P > 0.05).ConclusionsWe have identified 3 loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.SignificanceThis is the first genome-wide association study on neck or shoulder pain. We have identified 3 genetic loci (an intergenic region in chromosome 17, the FOXP2 gene in chromosome 7, and the LINC01572 gene in chromosome 16) that are associated with neck or shoulder pain using the UK Biobank cohort, among which the FOXP2 gene and the LINC01572 gene were weakly replicated by the Generation Scotland: Scottish Family Health Study (P < 0.05). The SNP heritability was 0.11, indicating neck or shoulder pain is a heritable trait. The tissue expression analysis suggested that neck or shoulder pain was related to multiple brain tissues, indicating the involvement of neuron function. The results will inform further research in the characterisation of the mechanisms of neck or shoulder pain.

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