Exome Sequencing in Venous Thromboembolic Disease Identifies Excess Mutation Burden in PROS1, PROC, SERPINC1 and STAB2

Abstract Deep vein thrombosis and pulmonary embolism, collectively referred to as venous thromboembolism (VTE), are the third leading cause of cardiovascular death in the United States. Genetic factors account for 50-60% of VTE risk and a recent meta-analysis of genome-wide association studies confirmed that common variants in F5, ABO, and seven other loci are associated with VTE. Rare mutations in the anticoagulant genes PROC, PROS1 and SERPINC1 have been linked to VTE in family studies. In order to identify new genetic variants altering the risk for VTE, we performed whole exome sequencing (WES) in 373 unrelated individuals of European ancestry with unprovoked VTE and compared results to a previously sequenced control cohort of 5784 unrelated Europeans. To avoid variant calling bias, only SNVs from exons with >10X coverage and less than 5% difference in coverage between cases and controls were included, removing 11,813 of 188,689 intervals. We used an emerging framework for a "collapsing" analysis on genes, defining qualifying variants on the basis of annotation and minor allele frequency <0.05%, and assumed a dominant model of inheritance. Tests were performed via a Fisher's exact test for a total of 11,585 CCDS genes. Strikingly, ranked by p-value, the top 4 genes were PROS1 (P= 2.01E-09, OR 11.8), STAB2 (P=2.70E-7, OR 3.37), PROC (P=3.24E-05, OR 11.0) and SERPINC1 (P=1.10E-04, OR 8.5). We detected 29 qualifying variants in 373 cases and 106 qualifying variants in 5784 controls in STAB2. This gene encodes Stabilin-2, which is a transmembrane glycoprotein scavenger receptor. Common variants at ABO are associated with VTE and are also known to regulate von Willebrand Factor (VWF) and coagulation Factor VIII (F8) plasma levels. Common variants in STAB2 are also associated with VWF/F8 levels in a large GWAS and with VTE risk in a smaller candidate gene study, suggesting that haploinsufficiency for Stabilin-2 may increase VTE risk through elevated levels of VWF/F8. Although replication and functional testing of these findings is warranted, this study demonstrates the utility of collapsing analyses using WES data to identify multiple loci harboring an excess of rare variants in individuals with a common complex disease trait. Disclosures Ginsburg: Shire: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: recombinant VWF and recombinant ADAMTS13; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

Scientific Reports ◽

10.1038/srep45040 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 51

Author(s):

Mathias Gorski ◽

Peter J. van der Most ◽

Alexander Teumer ◽

Audrey Y. Chu ◽

Man Li ◽

...

Keyword(s):

Kidney Function ◽

Kidney Development ◽

Association Studies ◽

Meta Analysis ◽

European Ancestry ◽

P Value ◽

Genome Wide Association Studies ◽

1000 Genomes ◽

Gene Sets ◽

Project Promise

Abstract HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

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Common variants at 5q33.1 predispose to migraine in African-American children

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105359 ◽

2018 ◽

Vol 55 (12) ◽

pp. 831-836 ◽

Cited By ~ 2

Author(s):

Xiao Chang ◽

Renata Pellegrino ◽

James Garifallou ◽

Michael March ◽

James Snyder ◽

...

Keyword(s):

African American ◽

Large Scale ◽

Association Studies ◽

Independent Study ◽

P Value ◽

African American Children ◽

Genome Wide Association Studies ◽

Common Variants ◽

Primary Analysis ◽

American Children

BackgroundGenome-wide association studies (GWASs) have identified multiple susceptibility loci for migraine in European adults. However, no large-scale genetic studies have been performed in children or African Americans with migraine.MethodsWe conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. We then attempted to replicate our primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects.ResultsThe results of this study indicate that common variants at 5q33.1 associated with migraine risk in African-American children (rs72793414, p=1.94×10−9). The association was validated in an independent study (p=3.87×10−3) for an overall meta-analysis p value of 3.81×10−10. eQTL (Expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1. NMUR2 encodes a G protein-coupled receptor of neuromedin-U (NMU). NMU, a highly conserved neuropeptide, participates in diverse physiological processes of the central nervous system.ConclusionsThis study provides new insights into the genetic basis of childhood migraine and allow for precision therapeutic development strategies targeting migraine patients of African-American ancestry.

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Genome-Wide Association Study Identifies Loci Associated with Sensitive Skin

Cosmetics ◽

10.3390/cosmetics7020049 ◽

2020 ◽

Vol 7 (2) ◽

pp. 49

Author(s):

Miranda A. Farage ◽

Yunxuan Jiang ◽

Jay P. Tiesman ◽

Pierre Fontanillas ◽

Rosemarie Osborne

Keyword(s):

Genome Wide Association Study ◽

Association Studies ◽

Genome Wide Association ◽

European Ancestry ◽

P Value ◽

Genome Wide Association Studies ◽

Online Questionnaire ◽

Sensitive Skin ◽

Genome Wide ◽

Skin Conditions

Individuals suffering from sensitive skin often have other skin conditions and/or diseases, such as fair skin, freckles, rosacea, or atopic dermatitis. Genome-wide association studies (GWAS) have been performed for some of these conditions, but not for sensitive skin. In this study, a total of 23,426 unrelated participants of European ancestry from the 23andMe database were evaluated for self-declared sensitive skin, other skin conditions, and diseases using an online questionnaire format. Responders were separated into two groups: those who declared they had sensitive skin (n = 8971) and those who declared their skin was not sensitive (controls, n = 14,455). A GWAS of sensitive skin individuals identified three genome-wide significance loci (p-value < 5 × 10−8) and seven suggestive loci (p-value < 1 × 10−6). Of the three most significant loci, all have been associated with pigmentation and two have been associated with acne.

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Interaction between Genetic Risk Scores for reduced pulmonary function and smoking, asthma and endotoxin

Thorax ◽

10.1136/thoraxjnl-2020-215624 ◽

2021 ◽

pp. thoraxjnl-2020-215624

Author(s):

Sinjini Sikdar ◽

Annah B Wyss ◽

Mi Kyeong Lee ◽

Thanh T Hoang ◽

Marie Richards ◽

...

Keyword(s):

Pulmonary Function ◽

Genetic Risk ◽

Association Studies ◽

European Ancestry ◽

Risk Scores ◽

P Value ◽

Genome Wide Association Studies ◽

Inverse Association ◽

Genetic Risk Scores ◽

Genome Wide

RationaleGenome-wide association studies (GWASs) have identified numerous loci associated with lower pulmonary function. Pulmonary function is strongly related to smoking and has also been associated with asthma and dust endotoxin. At the individual SNP level, genome-wide analyses of pulmonary function have not identified appreciable evidence for gene by environment interactions. Genetic Risk Scores (GRSs) may enhance power to identify gene–environment interactions, but studies are few.MethodsWe analysed 2844 individuals of European ancestry with 1000 Genomes imputed GWAS data from a case–control study of adult asthma nested within a US agricultural cohort. Pulmonary function traits were FEV1, FVC and FEV1/FVC. Using data from a recent large meta-analysis of GWAS, we constructed a weighted GRS for each trait by combining the top (p value<5×10−9) genetic variants, after clumping based on distance (±250 kb) and linkage disequilibrium (r2=0.5). We used linear regression, adjusting for relevant covariates, to estimate associations of each trait with its GRS and to assess interactions.ResultsEach trait was highly significantly associated with its GRS (all three p values<8.9×10−8). The inverse association of the GRS with FEV1/FVC was stronger for current smokers (pinteraction=0.017) or former smokers (pinteraction=0.064) when compared with never smokers and among asthmatics compared with non-asthmatics (pinteraction=0.053). No significant interactions were observed between any GRS and house dust endotoxin.ConclusionsEvaluation of interactions using GRSs supports a greater impact of increased genetic susceptibility on reduced pulmonary function in the presence of smoking or asthma.

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Abstract 13286: Finding the Missing Heritability of Serum Lipids: Leveraging the Relatedness in a Large-scale Biobank

Circulation ◽

10.1161/circ.142.suppl_3.13286 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Hung-hsin Chen ◽

Ryan J Bohlender ◽

Lauren E Petty ◽

Quinn Wells ◽

Chad Huff ◽

...

Keyword(s):

Serum Lipids ◽

Large Scale ◽

Association Studies ◽

Low Frequency ◽

The United States ◽

Lipid Lowering ◽

P Value ◽

Genome Wide Association Studies ◽

High Heritability ◽

Genomic Regions

Introduction: High prevalence of dyslipidemia in the United States results in elevated risk of cardiovascular disease. Although the high heritability of serum lipids has motivated many genome-wide association studies (GWAS), much of the heritability is still unexplained. Genomic regions shared with identity by descent (IBD) are inherited from the same common ancestor without recombination, and can be observed in both close and distant relatives. IBD segments provide an opportunity to discover genes that harbor low frequency, large effect variants that are undetectable in GWAS due to low power at rare and heterogeneous alleles. Methods: The Vanderbilt biobank (BioVU) comprises over 280,000 DNA samples from participants with linked electronic medical record (EMR). In this study, we extracted 18,337 European dyslipidemia cases, who have either diagnosed dyslipidemia or record of taking lipid-lowering drugs in linked EMR, and 18,337 sex, age, and ancestry-matched controls. The pairwise IBD shared segments were identified by GERMLINE using genotype data. To assess enrichment of IBD, we compared local shared IBD rates in case-case pairs and case-control pairs. Results: The greatest enrichment of IBD sharing was found on chromosome 5 (chr5: 169-171 MB, p-value=3.3х10 -5 ), and another three suggested regions were from chromosome 10, 18 and 22 (chr10: 86-87 MB, p-value=5.5х10 -4 , chr18: 10-11 MB, p-value=5.3х10 -4 , and chr22: 49.3-49.7 MB, p-value=2.1х10 -4 ). To further explore the molecular function, we used PrediXcan to impute the genetically regulated expression of the genes which locate within 1 MB of identified regions. A total of 31 unique genes in these regions exhibit significantly different predicted expression between risk IBD segment carriers and non-carriers, and are also significantly correlated with at least one serum lipids level. For instance, a novel long non-coding RNA, LINC01310, from chr22 associated with total glyceride (p-value=5.3х10 - 3 ) and expressed a lower level in risk people carrying the risk-associated IBD segment (p-value=1.2х10 - 6 ). Conclusions: Our results identity four genomic segments enriched in dyslipidemia cases, and, using GReX, we demonstrate the potential function of novel genes on the regulation of serum lipids.

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Mitofusin2 (MFN2) Preserves Mitochondrial Integrity and Function in Megakaryocytes and Platelets

Blood ◽

10.1182/blood-2021-154329 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3137-3137

Author(s):

Shancy P Jacob ◽

Yasuhiro Kosaka ◽

Seema Bhatlekar ◽

Alexandra Moody ◽

Victoria Moody ◽

...

Keyword(s):

Board Of Directors ◽

Complex I ◽

Association Studies ◽

Ischemia Reperfusion ◽

Ros Generation ◽

Genome Wide Association Studies ◽

Advisory Committees ◽

Human Cord Blood ◽

Mitochondrial Functions ◽

And Function

Abstract Genome wide association studies (GWAS) have associated mitochondria related loci with platelet numbers, function, and CVD. However, causality has not been established for many of these variants, and their mechanism and functional consequences are unknown. One such variant, MFN2 eQTL rs1474868 (T/T), has been associated with reduced platelet counts and reduced expression (5 fold) of MFN2 RNA in platelets. We show here that the MFN2 T/T variant corresponds with significantly reduced MFN2 protein in platelets. This difference contributes to a significant correlation between MFN2 RNA levels and mitochondrial load and potential in platelets. MFN2 RNA is also reduced by T/T in human cord blood derived megakaryocytes resulting in unfused mitochondria and impaired megakaryopoiesis. Using platelet/megakaryocyte specific Mfn2-/- (Mfn2 KO) mice, we show that Mfn2 impacts platelet numbers, activation and function by regulating mitochondrial energetics. Platelets without Mfn2 had reduced mitochondrial membrane potential and significantly reduced platelet lifespan (P<0.01) that was attributed to an increased rate of phosphatidylserine (PS) flipping (P=0.01). Increased RNA expression with conversely reduced protein expression of Ndufb8 (P<0.01), an index nuclear encoded complex I subunit that is stable only in a fully assembled complex I, suggested a defect in complex I assembly in Mfn2 KO platelets. Furthermore, complex I activity was reduced in Mfn2 KO platelets compared to WT platelets (P<0.01). Both basal and thrombin triggered mitochondrial oxygen consumption rate as assessed by Seahorse analyzer was significantly reduced in Mfn2 KO platelets (1.28 pmol/min/µg protein) compared to WT control platelets (3.06 pmol/min/µg protein). Platelet activation was subtly, yet significantly, decreased in Mfn2 KO platelets compared to WT platelets as assessed by surface expression of activated integrin alpha2b/beta3 and P-selectin. In addition, Mfn2 KO platelets had impaired Ca 2+ signaling, ROS generation, and procoagulant platelet formation (PS +ve platelets), and formed fewer platelet-neutrophil aggregates (PNAs) compared to WT platelets (P=0.01). Consistent with this, we observed significantly prolonged bleeding times in Mfn2 KO mice compared to their WT control littermates (P=0.001). Finally, mice with loss of platelet Mfn2 exhibited a modest reduction in ischemic stroke infarct size after cerebral ischemia-reperfusion that was statistically significant (P<0.01). Taken together these results suggest that MFN2 preserves mitochondrial functions necessary for platelet survival and activity, and that loss of MFN2 leads to accelerated platelet death, dysfunction, and altered hemostasis and thrombosis. Disclosures Rondina: Novartis: Research Funding; Platelet Biogenesis: Membership on an entity's Board of Directors or advisory committees; Acticor Biotech: Membership on an entity's Board of Directors or advisory committees; Platelet Transcriptomics: Patents & Royalties.

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Educational attainment reduces the risk of suicide attempt among individuals with and without psychiatric disorders independent of cognition: a bidirectional and multivariable Mendelian randomization study with more than 815,000 participants

Translational Psychiatry ◽

10.1038/s41398-020-01047-2 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Daniel B. Rosoff ◽

Zachary A. Kaminsky ◽

Andrew M. McIntosh ◽

George Davey Smith ◽

Falk W. Lohoff

Keyword(s):

Suicide Attempt ◽

Educational Attainment ◽

Psychiatric Disorders ◽

Mendelian Randomization ◽

Association Studies ◽

The United States ◽

European Ancestry ◽

Independent Effect ◽

Genome Wide Association Studies ◽

Causal Nature

Abstract Rates of suicidal behavior are increasing in the United States and identifying causal risk factors continues to be a public health priority. Observational literature has shown that educational attainment (EA) and cognitive performance (CP) influence suicide attempt risk; however, the causal nature of these relationships is unknown. Using summary statistics from genome-wide association studies (GWAS) of EA, CP, and suicide attempt risk with > 815,000 combined white participants of European ancestry, we performed multivariable Mendelian randomization (MR) to disentangle the effects of EA and CP on attempted suicide. In single-variable MR (SVMR), EA and CP appeared to reduce suicide attempt risk (EA odds ratio (OR) per standard deviation (SD) increase in EA (4.2 years), 0.524, 95% CI, 0.412–0.666, P = 1.07 × 10−7; CP OR per SD increase in standardized score, 0.714, 95% CI, 0.577–0.885, P = 0.002). Conversely, bidirectional analyses found no effect of a suicide attempt on EA or CP. Using various multivariable MR (MVMR) models, EA seems to be the predominant risk factor for suicide attempt risk with the independent effect (OR, 0.342, 95% CI, 0.206–0.568, P = 1.61 × 10−4), while CP had no effect (OR, 1.182, 95% CI, 0.842–1.659, P = 0.333). In additional MVMR analyses accounting simultaneously for potential behavioral and psychiatric mediators (tobacco smoking; alcohol consumption; and self-reported nerves, tension, anxiety, or depression), the effect of EA was little changed (OR, 0.541, 95% CI, 0.421–0.696, P = 3.33 × 10−6). Consistency of results across complementary MR methods accommodating different assumptions about genetic pleiotropy strengthened causal inference. Our results show that even after accounting for psychiatric disorders and behavioral mediators, EA, but not CP, may causally influence suicide attempt risk among white individuals of European ancestry, which could have important implications for health policy and programs aimed at reducing the increasing rates of suicide. Future work is necessary to examine the EA–suicide relationship populations of different ethnicities.

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Cross-Ethnic Meta-Analysis of Genetic Variants for Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2495 ◽

2013 ◽

Vol 98 (12) ◽

pp. E2006-E2012 ◽

Cited By ~ 59

Author(s):

Yvonne V. Louwers ◽

Lisette Stolk ◽

André G. Uitterlinden ◽

Joop S. E. Laven

Keyword(s):

Polycystic Ovary Syndrome ◽

Genetic Variants ◽

Polycystic Ovary ◽

Meta Analysis ◽

The United States ◽

European Ancestry ◽

P Value ◽

Genome Wide Association Studies ◽

Ovary Syndrome ◽

Northern European

Context: Genome-wide association studies (GWAS) have revealed new susceptibility loci for Chinese patients with polycystic ovary syndrome (PCOS). Because ethnic background adds to phenotypic diversities in PCOS, it seems plausible that genetic variants associated with PCOS act differently in various ethnic populations. Objective: We studied cross-ethnic effects of Chinese PCOS loci (ie, LHCGR, THADA, DENND1A, FSHR, c9orf3, YAP1, RAB5B/SUOX, HMGA2, TOX3, INSR, SUMO1P1) in patients of Northern European descent. Design: This study was a genetic association study conducted at an University Medical Center. Patients: Association was studied in 703 Dutch PCOS patients and 2164 Dutch controls. To assess the cross-ethnic effect, we performed a meta-analysis of the Dutch data combined with results of previously published studies in PCOS patients from China (n = 2254) and the United States (n = 2618). Adjusted for multiple testing, a P value <3.1 × 10−3 was considered statistically significant. Results: Meta-analysis of the Chinese, US, and Dutch data resulted in 12 significant variants mapping to the YAP1 (P value = 1.0× 10−9), RAB5B/SUOX (P value = 3.8 × 10−11), LHCGR (P value = 4.1 × 10−4), THADA (P value = 2.2 × 10−4 and P value = 1.3 × 10−3), DENND1A (P value = 2.3 × 10−3 and P value = 2.5 × 10−3), FSHR (P value = 3.8 × 10−5 and P value = 3.6 × 10−4), c9orf3 (P value = 2.0 × 10−6 and P value = 9.2 × 10−6), SUMO1P1 (P value = 2.3 × 10−3) loci with odds ratios ranging from 1.19 to 1.45 and 0.79 to 0.87. Conclusions: Overall, we observed for 12 of 17 genetic variants mapping to the Chinese PCOS loci similar effect size and identical direction in PCOS patients from Northern European ancestry, indicating a common genetic risk profile for PCOS across populations. Therefore, it is expected that large GWAS in PCOS patients from Northern European ancestry will partly identify similar loci as the GWAS in Chinese PCOS patients.

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Powerful statistical method to detect disease associated genes using publicly available GWAS summary data

10.1101/478321 ◽

2018 ◽

Cited By ~ 3

Author(s):

Jianjun Zhang ◽

Zihan Zhao ◽

Xuan Guo ◽

Bin Guo ◽

Baolin Wu

Keyword(s):

Cell Function ◽

Association Studies ◽

P Value ◽

Type I ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Common Variants ◽

Single Marker Analysis ◽

Adaptive Combination ◽

Single Marker

Genome-wide association studies (GWAS) have thus far achieved substantial success. In the last decade a large number of common variants underlying complex diseases have been identified through GWAS. In most existing GWAS, the identified common variants are obtained by single marker based tests, that is, testing one single nucleotide polymorphisms (SNP) at a time. Generally the basic functional unit of inheritance is a gene, rather than a SNP. Thus, results from gene level association test can be more readily integrated with downstream functional and pathogenic investigation. In this paper, we propose a general gene-based p-value adaptive combination approach (GPA) which can integrate association evidence of multiple genetic variants using only GWAS summary statistics (either p-value or other test statistics). The proposed method could be used to test both continuous and binary traits through not only a single but also multiple studies, which helps overcome the limitation of existing methods that only can be applied to specific type of data. We conducted thorough simulation studies to verify that the proposed method controls type I errors well, and performs favorably compared to single-marker analysis and other existing methods. We demonstrated the utility of our proposed method through analysis of GWAS meta-analysis results for fasting glucose and lipids from the international MAGIC consortium and Global Lipids Consortium, respectively. The proposed method identified some novel traits associated genes which can improve our understanding of the mechanisms involved in β-cell function, glucose homeostasis and lipids traits.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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