scholarly journals Genome-wide meta-analysis of cognitive empathy: heritability, and correlates with sex, neuropsychiatric conditions and brain anatomy

2016 ◽  
Author(s):  
Varun Warrier ◽  
Katrina Grasby ◽  
Florina Uzefovsky ◽  
Roberto Toro ◽  
Paula Smith ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Cognitive Empathy ◽  
European Ancestry ◽  
Brain Anatomy ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Cognitive Aptitude ◽  
Genome Wide ◽  
A Genome ◽  
Research Volunteers

We conducted a genome-wide meta-analysis of cognitive empathy using the ‘Reading the Mind in the Eyes’ Test (Eyes Test) in 88,056 research volunteers of European Ancestry (44,574 females and 43,482 males) from 23andMe Inc., and an additional 1,497 research volunteers of European Ancestry (891 females and 606 males) from the Brisbane Longitudinal Twin Study (BLTS). We confirmed a female advantage on the Eyes Test (Cohen’s d = 0.21, P < 2.2x10−16), and identified a locus in 3p26.1 that is associated with scores on the Eyes Test in females (rs7641347, Pmeta = 1.58 x 10−8). Common single nucleotide polymorphisms (SNPs) explained 5.8% (95% CI: 0.45 - 0.72; P = 1.00 x 10−17) of the total trait variance in both sexes, and we identified a twin heritability of 0.28 (95% CI: 0.13-0.42). Finally, we identified significant genetic correlation between the Eyes Test and anorexia nervosa, measures of empathy (the Empathy Quotient), openness (NEO-Five Factor Inventory), and different measures of educational attainment and cognitive aptitude, and show that the genetic determinants of volumes of the dorsal striatum (caudate nucleus and putamen) are positively correlated with the genetic determinants of performance on the Eyes Test.

scholarly journals KCND3 is a novel susceptibility locus for early repolarization

2019 ◽  
Author(s):  
Alexander Teumer ◽  
Teresa Trenkwalder ◽  
Thorsten Kessler ◽  
Yalda Jamshidi ◽  
Marten E. van den Berg ◽  
...  
Keyword(s):  
Association Studies ◽  
Meta Analysis ◽  
European Ancestry ◽  
Strong Linkage Disequilibrium ◽  
Genome Wide Association Studies ◽  
Pathophysiological Mechanism ◽  
Genetic Determinants ◽  
Early Repolarization ◽  
Genome Wide ◽  
A Genome

AbstractThe presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D’=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

scholarly journals Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jaakko Laaksonen ◽  
Pashupati P. Mishra ◽  
Ilkka Seppälä ◽  
Leo-Pekka Lyytikäinen ◽  
Emma Raitoharju ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mitochondrial Dna ◽  
Genome Wide Association Study ◽  
Rare Variants ◽  
Meta Analysis ◽  
Noncommunicable Diseases ◽  
Nucleotide Polymorphisms ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Mitochondrial Dna Variants

AbstractHigh blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

scholarly journals Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry

2018 ◽  
Vol 28 (1) ◽  
pp. 166-174 ◽  
Author(s):  
Sara L Pulit ◽  
Charli Stoneman ◽  
Andrew P Morris ◽  
Andrew R Wood ◽  
Craig A Glastonbury ◽  
...  
Keyword(s):  
Body Fat ◽  
Association Studies ◽  
Meta Analysis ◽  
Fat Distribution ◽  
Body Fat Distribution ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome

Abstract More than one in three adults worldwide is either overweight or obese. Epidemiological studies indicate that the location and distribution of excess fat, rather than general adiposity, are more informative for predicting risk of obesity sequelae, including cardiometabolic disease and cancer. We performed a genome-wide association study meta-analysis of body fat distribution, measured by waist-to-hip ratio (WHR) adjusted for body mass index (WHRadjBMI), and identified 463 signals in 346 loci. Heritability and variant effects were generally stronger in women than men, and we found approximately one-third of all signals to be sexually dimorphic. The 5% of individuals carrying the most WHRadjBMI-increasing alleles were 1.62 times more likely than the bottom 5% to have a WHR above the thresholds used for metabolic syndrome. These data, made publicly available, will inform the biology of body fat distribution and its relationship with disease.

Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

2020 ◽  
Vol 105 (12) ◽  
pp. 3854-3864
Author(s):  
Jin-Fang Chai ◽  
Shih-Ling Kao ◽  
Chaolong Wang ◽  
Victor Jun-Yu Lim ◽  
Ing Wei Khor ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Hba1c Level ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Specific Reference ◽  
Genetic Determinants ◽  
Genome Wide ◽  
Whole Exome ◽  
A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P &lt; 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

scholarly journals The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

2020 ◽  
Author(s):  
David Ellinghaus ◽  
Frauke Degenhardt ◽  
Luis Bujanda ◽  
Maria Buti ◽  
Agustín Albillos ◽  
...  
Keyword(s):  
Respiratory Failure ◽  
Blood Group ◽  
Association Analysis ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Nucleotide Polymorphisms ◽  
Genome Wide Association Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Group Locus

ABSTRACTBackgroundRespiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients.MethodsWe included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels.ResultsWe detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5×10−8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14×10−10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95×10−8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48×10−4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06×10−5).ConclusionsWe herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

scholarly journals Meta-Analysis of Hodgkin Lymphoma and Asthma Genome-Wide Association Scans reveals common variants in GATA3

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 135-135
Author(s):  
Yinfei Kong ◽  
Pouya Khankhanian ◽  
Daniel Himmelstein ◽  
Amie E. Hwang ◽  
Kristin A Rand ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Meta Analysis ◽  
Gwas Data ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Significance Level ◽  
Nodular Sclerosis ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Significance

Abstract Both Hodgkin lymphoma (HL) and asthma are associated with relative isolation from early childhood infectious exposures (hygiene hypothesis) and a T-helper-2 (Th2)-skewed immune response. To test the hypothesis that there is some component of shared genetic etiology between HL and asthma, we examined the genetic overlap in data from genome-wide association study (GWAS) meta-analyses of the two diseases conducted in populations of European ancestry. The HL GWAS meta-analysis consisted of 1,816 HL cases and 7,877 controls, and the asthma GWAS meta-analysis consisted of 2,088 asthma cases and 2,743 controls. The combined HL-asthma GWAS data resulted in 904,634 common single nucleotide polymorphisms (SNPs) genotyped with both arrays. We observed a total of 9 common SNPs associated with both HL and asthma at p<0.0001, compared to 3 SNPs expected in both data sets at that significance level. Out of 66 genetic risk variants associated with HL at a genome-wide significance level of p<10-8, 5 variants replicated in the asthma GWAS dataset at p < 0.05. In a meta-analysis combining the HL and asthma GWAS data, we found genome-wide significant associations with two correlated SNPs (r2 =0.91) in the Th2 transcription factor gene GATA3 (rs422628, ORHL-asthma meta =1.25, p=3.36 x 10-9 and rs444929, ORHL-asthma meta = 1.26, p=2.09 x 10-8) that were not genome-wide significant in either disease alone (Table 1). The association with one SNP remained genome-wide significant in the meta-analysis combined with the nodular sclerosis subset (rs422628, ORHL-asthma meta =1.32, p=3.75 x 10-9), but not with other HL subtypes. An association with a SNP in IKZF3, a gene involved in B lymphocyte differentiation and proliferation, reached genome-wide significance only in the meta-analysis with the HL subset positive for Epstein-Barr virus (EBV) in the tumor (rs9909593, ORHL-asthma meta = 1.19, p=3.80 x 10-8). In a genetic diseasome analysis based on an ontological analysis of published GWAS data, HL, especially nodular sclerosis HL, was more closely related to asthma than to solid cancers. Recognition of overlap in genetic predisposition to HL and other immune diseases sheds light on the complex etiology of HL and may enable novel diagnostic and therapeutic approaches. Abstract 135. Table 1 Genome-wide significant results of a meta-analysis combining Hodgkin lymphoma (HL) and asthma GWAS1data. HL GWAS1 Asthma GWAS1 Combined GWAS1 SNP2 Chr3 BP4 Gene OR5 P-value6 OR5 P-value6 OR5 P-value6 rs422628a 10 8151415 GATA3 1.24 1.13 x 10-5 1.31 6.39 x10-5 1.25 3.26 x 10-9 rs444929b 10 8150030 GATA3 1.26 3.24x 10-6 1.28 8.90 x 10-4 1.26 2.09 x 10-8 rs422628c 10 8151415 GATA3 1.33 7.77 x 10-6 1.31 6.39 x10-5 1.32 3.75 x 10-9 rs9909593d 17 35223675 IKZF3 1.11 2.60 x 10-1 1.25 5.06 x 10-8 1.19 3.80 x 10-8 1Genome-wide association scan 2Single nucleotide polymorphism 3Chromosome 4Base pair position 5Odds ratio 6P-values are derived from a meta-analysis using a fixed effects model with weights proportional to the square root of the number of cases. aAll Hodgkin lymphoma cases bAll Hodgkin lymphoma cases, SNP association reported in Cozen et al., Nat Comm, 2014 cNodular sclerosis cases only dEBV-positive cases only Disclosures No relevant conflicts of interest to declare.

Genetic determinants of chronic oxaliplatin-induced peripheral neurotoxicity: a genome-wide study replication and meta-analysis

2015 ◽  
Vol 20 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Salvatore Terrazzino ◽  
Andreas A. Argyriou ◽  
Sarah Cargnin ◽  
Anna G. Antonacopoulou ◽  
Chiara Briani ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Genetic Determinants ◽  
Peripheral Neurotoxicity ◽  
Genome Wide ◽  
A Genome ◽  
Genome Wide Study

scholarly journals Associations of Lipid-related SNPs with Circulating Phylloquinone Are Proportional with Triglycerides (P15-008-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jennifer Kelly ◽  
Hassan Dashti ◽  
Jose M Ordovas ◽  
Gregory Matuszek ◽  
Caren Smith ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Agricultural Research ◽  
Meta Analysis ◽  
Genetic Risk Score ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Summary Statistics ◽  
Linear Association ◽  
Genome Wide ◽  
A Genome

Abstract Objectives Phylloquinone is transported on triglyceride-rich lipoproteins. Preliminary evidence from a genome-wide association meta-analysis suggests that genetic variants that influence triglycerides (TGs), such as rs964184 at the APOA1/C3/A4/A5 gene cluster, also influence circulating phylloquinone. To further evaluate this overlap, we examined the linear relationship between a weighted TG genetic risk score (wTG-GRS) with circulating phylloquinone. Methods We constructed a wTG-GRS comprised of 20 SNPs that were previously associated with TGs in a genome-wide association meta-analysis for blood lipids (n > 188,000 individuals of European ancestry). The assigned weights corresponded to the effect-sizes (β) reported for each SNP's association with TGs. With meta-analytic summary statistic data from a separate genome-wide association meta-analysis of circulating phylloquinone (n = 2138 individuals of European ancestry), a statistical technique was used to approximate the linear association of the wTG-GRS with circulating phylloquinone. A p-value of 0.05 for the estimate was considered statistically significant. First, the estimate was calculated without adjustment for TGs using Model 1 summary statistics, then calculated with adjustment for TGs using Model 2 summary statistics. Results The estimate for the linear association of the wTG-GRS with circulating phylloquinone was significant without and with adjustment for TGs (Model 1: β = 0.052, P = < 0.0001, Model 2: β = 0.027, P = 0.0001, respectively). The goodness-of-fit of the model was improved from Model 1 (p-het = 0.022) to Model 2 (p-het = 0.054). Conclusions The associations of TG-related SNPs with circulating phylloquinone were proportional to their associations with TGs. This provides further evidence of the shared genetic links between TGs and phylloquinone and suggests genetic studies of vitamin K should consider TGs. Funding Sources Study supported by the USDA Agricultural Research Service under Cooperative Agreement No. 58-1950-7-707 and NHLBI T32HL069772.

scholarly journals A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Ryoichi Nakamura ◽  
Kazuharu Misawa ◽  
Genki Tohnai ◽  
Masahiro Nakatochi ◽  
Sho Furuhashi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Japanese Population ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
European Ancestry ◽  
Japanese Cohort ◽  
Genome Wide ◽  
Sporadic Als ◽  
A Genome ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

scholarly journals Genome-Wide Association between the 2q33.1 Locus and Intracranial Aneurysm Susceptibility: An Updated Meta-Analysis Including 18,019 Individuals

2019 ◽  
Vol 8 (5) ◽  
pp. 692
Author(s):  
Eun Pyo Hong ◽  
Bong Jun Kim ◽  
Jin Pyeong Jeon
Keyword(s):  
Intracranial Aneurysm ◽  
Association Studies ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Eqtl Analysis ◽  
Genome Wide Association Studies ◽  
Human Tissues ◽  
Genome Wide ◽  
A Genome

Previous genome-wide association studies did not show a consistent association between the BOLL gene (rs700651, 2q33.1) and intracranial aneurysm (IA) susceptibility. We aimed to perform an updated meta-analysis for the potential IA-susceptibility locus in large-scale multi-ethnic populations. We conducted a systematic review of studies identified by an electronic search from January 1990 to March 2019. The overall estimates of the “G” allele of rs700651, indicating IA susceptibility, were calculated under the fixed- and random-effect models using the inverse-variance method. Subsequent in silico function and cis-expression quantitative trait loci (cis-eQTL) analyses were performed to evaluate biological functions and genotype-specific expressions in human tissues. We included 4513 IA patients and 13,506 controls from five studies with seven independent populations: three European-ancestry, three Japanese, and one Korean population. The overall result showed a genome-wide significance threshold between rs700651 and IA susceptibility after controlling for study heterogeneity (OR = 1.213, 95% CI: 1.135–1.296). Subsequent cis-eQTL analysis showed significant genome-wide expressions in three human tissues, i.e., testis (p = 8.04 × 10−15 for ANKRD44), tibial nerves (p = 3.18 × 10−10 for SF3B1), and thyroid glands (p = 4.61 × 10−9 for SF3B1). The rs700651 common variant of the 2q33.1 region may be involved in genetic mechanisms that increase the risk of IA and may play crucial roles in regulatory functions.

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