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

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.

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Genome-Wide Association study Identifies a Novel Association Between a Cardiovascular Gene Polymorphism and Superior Athletic Performance

University of the Future: Re-Imagining Research and Higher Education ◽

10.29117/quarfe.2020.0111 ◽

2020 ◽

Author(s):

Mohamed Elrayess ◽

Fatima Al-Khelaifi ◽

Noha Yousri ◽

Omar Al-Bagha

Keyword(s):

Athletic Performance ◽

Genome Wide Association Study ◽

Endurance Athlete ◽

Meta Analysis ◽

Significant Snps ◽

Nucleotide Polymorphisms ◽

Replication Studies ◽

Genome Wide ◽

Small Effect Size ◽

Metabolomics Analysis

Research into the genetic predisposition to superior athletic performance has been a hindered by the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. Results: The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high (n=662) and low/moderate (n=134) aerobic component. Validation of results was performed by comparing the frequencies of the most significant SNPs between 242 and 168 elite Russian high and low/moderate aerobic athletes, respectively, and between 60 elite Japanese endurance athletes and 406 controls. A meta-analysis has identified rs1052373 (GG homozygotes) in Myosin Binding Protein (MYBPC3; implicated in cardiac hypertrophic myopathy) gene to be associated with endurance athlete status (P=1.43E-08, odd ratio 2.2). Homozygotes carriers of rs1052373 G allele in Russian athletes had significantly greater VO2max than carriers of the AA+AG (P = 0.005). Subsequent metabolomics analysis revealed several amino acids and lipids associated with rs1052373 G allele (1.82x10-05) including the testosterone precursor androstenediol (3beta, 17beta) disulfate. Conclusion: This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted.

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa658 ◽

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 < 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.

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

10.1101/081844 ◽

2016 ◽

Cited By ~ 2

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.

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Abstract 54: Genome-Wide Association Analysis of Gene-Sodium Interactions on Blood Pressure Phenotypes: The GenSalt Study

Circulation ◽

10.1161/circ.131.suppl_1.54 ◽

2015 ◽

Vol 131 (suppl_1) ◽

Author(s):

Changwei Li ◽

Jiang He ◽

James Hixson ◽

Dongfeng Gu ◽

Dabeeru Rao ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Intake ◽

Meta Analysis ◽

Snp Array ◽

Urinary Sodium Excretion ◽

Dietary Sodium ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Inverse Variance ◽

Meta Analyses

Background: Elevated blood pressure (BP) is a major public health challenge. Although the heritability of BP has been long established, current findings can explain only a small proportion of the BP variability attributed to genetic factors. Recent studies indicate that gene-environmental interactions may help to identify novel BP loci. Hence, the current study aimed to identify genetic variants influencing BP regulation by conducting genome-wide gene-sodium interaction analyses among 1,906 participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Methods: GenSalt recruited 1,906 Chinese participants from 633 families. At baseline, one 24-hour and two 8-hour urine specimens were collected to measure urinary sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 868,158 autosomal single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genomewide Human SNP array 6.0 (Affymetrix, Inc, Santa Clara, CA). Mixed effects models were used to test genome-wide SNP-sodium interactions on BP, adjusting for age, gender, and body mass index. Promising findings (interaction term P <1.00х10 -6 ) from GenSalt were further evaluated for replication among Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with available data from the database of genotypes and phenotypes (dbGaP). SNP effects in GenSalt and MESA were meta-analyzed using inverse-variance weighted fixed effect models. Results: The meta-analyses identified 3 novel loci that significantly interacted with sodium to influence BP phenotypes. SNP-sodium interactions on systolic BP were identified for NEK2 variant rs10494938 at 1q32.3 (GenSalt P =2.19х10 -6 , MESA P =4.35х10 -4 , and Meta-analysis P = 3.93х10 -8 ). In addition, CASP4 variant rs1944900 at 11q22.3 interacted with sodium to influence both systolic BP (GenSalt P =1.24х10 -9 , MESA P =4.22х10 -2 , and Meta-analysis P = 1.14х10 -10 ) and mean arterial pressure (GenSalt P =1.68х10 -9 , MESA P =4.27х10 -2 , and Meta-analysis P = 1.91х10 -10 ). Furthermore, C9orf3 variant rs17679141 at 9q22.32 interacted with sodium to influence diastolic BP (GenSalt P =2.85х10 -8 , MESA P =4.55х10 -2 , and Meta-analysis P =4.61х10 -9 ). The 3 variants all physically mapped to the intronic regions of their corresponding genes. Conclusion: The current study identified 3 novel loci which may interact with dietary sodium intake to influence BP phenotypes.

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Modifiable risk factors for intracranial aneurysms: Evidence from genetic studies

International Journal of Stroke ◽

10.1177/17474930211065640 ◽

2022 ◽

pp. 174749302110656

Author(s):

Xiaohui Sun ◽

Bin Liu ◽

Ying Chen ◽

Linshuoshuo Lv ◽

Ding Ye ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Educational Attainment ◽

Genome Wide Association Study ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Health Concern ◽

Modifiable Risk Factors ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

A Genome

Background: Intracranial aneurysm (IA) is a crucial health concern with limited strategies for prevention and treatment. Aim: To identify potentially modifiable risk factors, such as socioeconomic, behaviors, dietary, and cardiometabolic factors, for IA and its subtypes. Methods: Summary statistics for IA were derived from a genome-wide association study with an overall 79,429 participants. Single nucleotide polymorphisms associated with modifiable risk factors at genome-wide significance ( P = 5 × 10–8) were used as instrumental variables. The inverse-variance-weighted method, weighted-median method, Mendelian randomization (MR)-Egger regression, MR-Pleiotropy RESidual Sum and Outlier, and multivariable MR analyses were performed to evaluate the effect estimates. Results: Genetically predicted educational attainment, insomnia, smoking, and systolic and diastolic blood pressure (SBP and DBP) were significantly associated with the risk of IA. The odds ratios (ORs) were 0.44 (95% confidence interval (CI): 0.37–0.52) for educational attainment, 1.15 (95% CI: 1.08–1.23) for insomnia, 1.56 (95% CI: 1.38–1.75) for smoking initiation, 2.69 (95% CI: 1.77–4.07) for cigarette per day, 2.65 (95% CI: 1.72–4.08) for lifetime smoking, 1.07 (95% CI: 1.06–1.09), and 1.06 (95% CI: 1.04–1.10) for SBP and DBP, respectively. Similar effect estimates were observed for unruptured IAs and aneurysmal subarachnoid hemorrhage. Conclusions: This study provided genetic evidence that several modifiable risk factors, including blood pressure, smoking, educational attainment, and insomnia were associated with the risk of IA.

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Genetic determinants of daytime napping and effects on cardiometabolic health

10.1101/2020.06.12.20129858 ◽

2020 ◽

Cited By ~ 1

Author(s):

Hassan S. Dashti ◽

Iyas Daghlas ◽

Jacqueline M. Lane ◽

Yunru Huang ◽

Miriam S. Udler ◽

...

Keyword(s):

Blood Pressure ◽

Drug Targets ◽

Genetic Basis ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Cardiometabolic Health ◽

Genetic Determinants ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractDaytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remains unclear. Here, we performed a genome-wide association study of self-reported daytime napping in the UK Biobank (n=452,633) and identified 123 loci of which 60 replicated in 23andMe research participants (n=541,333). Findings included missense variants in established drug targets (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Signals were concordant with accelerometer-measured daytime inactivity duration and 33 signals colocalized with signals for other sleep phenotypes. Cluster analysis identified 3 clusters suggesting distinct nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization showed potential causal links between more frequent daytime napping and higher systolic blood pressure, diastolic blood pressure, and waist circumference.

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Genome-wide association study identifies new loci associated with noise-induced tinnitus in Chinese populations

BMC Genomic Data ◽

10.1186/s12863-021-00987-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Chengyong Xie ◽

Yuguang Niu ◽

Jie Ping ◽

Yahui Wang ◽

Chenning Yang ◽

...

Keyword(s):

Association Study ◽

Noise Exposure ◽

Genome Wide Association Study ◽

Acoustic Stimulus ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Genetic Determinants ◽

Chinese Populations ◽

Genome Wide ◽

Susceptibility To Noise

Abstract Background Tinnitus is an auditory phantom sensation in the absence of an acoustic stimulus, which affects nearly 15% of the population. Excessive noise exposure is one of the main causes of tinnitus. To now, the knowledge of the genetic determinants of susceptibility to tinnitus remains limited. Results We performed a two-stage genome-wide association study (GWAS) and identified that two single nucleotide polymorphisms (SNPs), rs2846071 located in the intergenic region at 11q13.5 (odds ratio [OR] = 2.14, 95% confidence interval [CI] = 1.96–3.40, combined P = 4.89 × 10− 6) and rs4149577 located in the intron of TNFRSF1A gene at 12p13.31 (OR = 2.05, 95% CI = 1.89–2.51, combined P = 6.88 × 10− 6), are significantly associated with the susceptibility to noise-induced tinnitus. Furthermore, the expression quantitative trait loci (eQTL) analyses revealed that rs2846071 is significantly correlated with the expression of WNT11 gene, and rs4149577 with the expression of TNFRSF1A gene in multiple brain tissues (all P < 0.05). The newly identified candidate gene WNT11 is involved in Wnt pathway, and TNFRSF1A in the tumor necrosis factor pathway, respectively. Pathway enrichment analyses also showed that these two pathways are closely relevant to tinnitus. Conclusions Our findings highlight two novel loci at 11q13.5 and 12p13.31 conferring susceptibility to noise-induced tinnitus. and suggest that the WNT11 and TNFRSF1A genes might be the candidate causal targets of 11q13.5 and 12p13.31 loci, respectively.

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Abstract 152: Genome-wide Association Study of Early-Onset Ischemic Stroke Identifies Novel Locus on Chromosome 12 Near BCL7A/MLXIP

Stroke ◽

10.1161/str.51.suppl_1.152 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Thomas Jaworek ◽

Steven J Kittner ◽

Christina Jern ◽

Frank Erik de Leeuw ◽

Martin Dichgans ◽

...

Keyword(s):

Blood Pressure ◽

Ischemic Stroke ◽

Effect Size ◽

Early Onset ◽

Drug Targets ◽

Genome Wide Association Study ◽

Meta Analysis ◽

European Ancestry ◽

Subtype Specificity ◽

Genome Wide

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets relevant to later-onset disease. Few studies have investigated the role of common genetic variation in the etiology of early-onset ischemic stroke (IS). Methods: We performed a GWAS meta-analysis of 38 studies from 10 countries, comprised of 5,847 IS cases of European ancestry under age 60 and 32,533 controls. Results: We identified two genome-wide significant (p< 5 x 10 -8 ) loci (see Figure). The ABO locus has previously been associated with venous thrombosis and ischemic stroke in predominantly older adults, but the effect size of our top SNP (OR 1.18; p = 9.1 x 10 -12 ) is larger than the effect size for this same SNP in MEGASTROKE (OR: 1.05; p = 6.5 x 10 -5 ). The lead SNP at the BCL7A/MLXIP locus is a novel GWAS finding for stroke (OR 1.14, 95% CI 1.08-1.19; p = 1.7 x 10 -8 ) and is noteworthy because of prior reports linking SNPs in these genes to BMI and blood pressure. Conclusions: We identified a novel locus that is near variants associated with BMI and blood pressure. Further studies are needed to confirm this locus, examine subtype specificity, and determine its function. The larger effect size observed at the ABO in this early-onset IS sample compared to older-onset IS samples is consistent with a larger role for prothrombotic mechanisms in early-onset IS.

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Mitochondrial genome-wide association study of migraine – the HUNT Study

Cephalalgia ◽

10.1177/0333102420906835 ◽

2020 ◽

Vol 40 (6) ◽

pp. 625-634 ◽

Cited By ~ 1

Author(s):

Sigrid Børte ◽

John-Anker Zwart ◽

Anne Heidi Skogholt ◽

Maiken Elvestad Gabrielsen ◽

Laurent F Thomas ◽

...

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Genome ◽

Association Study ◽

Genome Wide Association Study ◽

Rare Variants ◽

Population Based ◽

Genome Wide Association ◽

Health Study ◽

Genome Wide ◽

Number Variation

Background Variation in mitochondrial DNA (mtDNA) has been indicated in migraine pathogenesis, but genetic studies to date have focused on candidate variants, with sparse findings. We aimed to perform the first mitochondrial genome-wide association study of migraine, examining both single variants and mitochondrial haplogroups. Methods In total, 71,860 participants from the population-based Nord-Trøndelag Health Study were genotyped. We excluded samples not passing quality control for nuclear genotypes, in addition to samples with low call rate and closely maternally related. We analysed 775 mitochondrial DNA variants in 4021 migraine cases and 14,288 headache-free controls, using logistic regression. In addition, we analysed 3831 cases and 13,584 controls who could be reliably assigned to a mitochondrial haplogroup. Lastly, we attempted to replicate previously reported mitochondrial DNA candidate variants. Results Neither of the mitochondrial variants or haplogroups were associated with migraine. In addition, none of the previously reported mtDNA candidate variants replicated in our data. Conclusions Our findings do not support a major role of mitochondrial genetic variation in migraine pathophysiology, but a larger sample is needed to detect rare variants and future studies should also examine heteroplasmic variation, epigenetic changes and copy-number variation.

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A genome-wide association study of reproduction traits in four pig populations with different genetic backgrounds

Asian-Australasian Journal of Animal Sciences ◽

10.5713/ajas.19.0411 ◽

2020 ◽

Vol 33 (9) ◽

pp. 1400-1410

Author(s):

Yao Jiang ◽

Shaoqing Tang ◽

Wei Xiao ◽

Peng Yun ◽

Xiangdong Ding

Keyword(s):

Association Study ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Nucleotide Polymorphisms ◽

Multiple Trait ◽

Multiple Populations ◽

Genome Wide ◽

A Genome ◽

Reproduction Traits

Objective: Genome-wide association study and two meta-analysis based on GWAS performed to explore the genetic mechanism underlying variation in pig number born alive (NBA) and total number born (TNB).Methods: Single trait GWAS and two meta-analysis (single-trait meta analysis and multitrait meta analysis) were used in our study for NBA and TNB on 3,121 Yorkshires from 4 populations, including three different American Yorkshire populations (n = 2,247) and one British Yorkshire populations (n = 874).Results: The result of single trait GWAS showed that no significant associated single nucleotide polymorphisms (SNPs) were identified. Using single-trait meta analysis and multi-trait meta analysis within populations, 11 significant loci were identified associated with target traits. Spindlin 1, vascular endothelial growth factor A, forkhead box Q1, msh homeobox 1, and LHFPL tetraspan submily member 3 are five functionally plausible candidate genes for NBA and TNB. Compared to the single population GWAS, single-trait Meta analysis can improve the detection power to identify SNPs by integrating information of multiple populations. The multiple-trait analysis reduced the power to detect trait-specific loci but enhanced the power to identify the common loci across traits.Conclusion: In total, our findings identified novel genes to be validated as candidates for NBA and TNB in pigs. Also, it enabled us to enlarge population size by including multiple populations with different genetic backgrounds and increase the power of GWAS by using meta analysis.

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