scholarly journals The genetic architecture of sporadic and recurrent miscarriage

2019 ◽  
Author(s):  
Triin Laisk ◽  
Ana Luiza G Soares ◽  
Teresa Ferreira ◽  
Jodie N Painter ◽  
Samantha Laber ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Large Scale ◽  
Recurrent Miscarriage ◽  
Meta Analysis ◽  
Chromosome 9 ◽  
Extravillous Trophoblast ◽  
European Ancestry ◽  
Association Analyses ◽  
Progesterone Production ◽  
Genome Wide

Miscarriage is a common complex trait that affects 10-25% of clinically confirmed pregnancies1,2. Here we present the first large-scale genetic association analyses with 69,118 cases from five different ancestries for sporadic miscarriage and 750 cases of European ancestry for recurrent miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association on chromosome 13 (rs146350366, minor allele frequency (MAF) 1.2%,Pmeta=3.2×-8(CI) 1.2-1.6) for sporadic miscarriage in our European ancestry meta-analysis (50,060 cases and 174,109 controls), located nearFGF9involved in pregnancy maintenance3and progesterone production4. Additionally, we identified three genome-wide significant associations for recurrent miscarriage, including a signal on chromosome 9 (rs7859844, MAF=6.4%,Pmeta=1.3×-8in controlling extravillous trophoblast motility5. We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability and, genetic correlation analyses. Our results implicate that miscarriage etiopathogenesis is partly driven by genetic variation related to gonadotropin regulation, placental biology and progesterone production.

scholarly journals The genetic architecture of sporadic and multiple consecutive miscarriage

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Triin Laisk ◽  
Ana Luiza G. Soares ◽  
Teresa Ferreira ◽  
Jodie N. Painter ◽  
Jenny C. Censin ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Genetic Architecture ◽  
Large Scale ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Complex Trait ◽  
Pregnancy Complication ◽  
European Ancestry ◽  
Association Analyses ◽  
Genome Wide

AbstractMiscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10−8, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10−8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10−9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10−8, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.

scholarly journals Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis

2020 ◽  
Vol 8 (1) ◽  
pp. e001140
Author(s):  
Xinpei Wang ◽  
Jinzhu Jia ◽  
Tao Huang
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Correlation ◽  
Genetic Architecture ◽  
Large Scale ◽  
Meta Analysis ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Shared Genetic

ObjectiveWe aimed to estimate genetic correlation, identify shared loci and test causality between leptin levels and type 2 diabetes (T2D).Research design and methodsOur study consists of three parts. First, we calculated the genetic correlation of leptin levels and T2D or glycemic traits by using linkage disequilibrium score regression analysis. Second, we conducted a large-scale genome-wide cross-trait meta-analysis using cross-phenotype association to identify shared loci between trait pairs that showed significant genetic correlations in the first part. In the end, we carried out a bidirectional MR analysis to find out whether there is a causal relationship between leptin levels and T2D or glycemic traits.ResultsWe found positive genetic correlations between leptin levels and T2D (Rg=0.3165, p=0.0227), fasting insulin (FI) (Rg=0.517, p=0.0076), homeostasis model assessment-insulin resistance (HOMA-IR) (Rg=0.4785, p=0.0196), as well as surrogate estimates of β-cell function (HOMA-β) (Rg=0.4456, p=0.0214). We identified 12 shared loci between leptin levels and T2D, 1 locus between leptin levels and FI, 1 locus between leptin levels and HOMA-IR, and 1 locus between leptin levels and HOMA-β. We newly identified eight loci that did not achieve genome-wide significance in trait-specific genome-wide association studies. These shared genes were enriched in pancreas, thyroid gland, skeletal muscle, placenta, liver and cerebral cortex. In addition, we found that 1-SD increase in HOMA-IR was causally associated with a 0.329 ng/mL increase in leptin levels (β=0.329, p=0.001).ConclusionsOur results have shown the shared genetic architecture between leptin levels and T2D and found causality of HOMA-IR on leptin levels, shedding light on the molecular mechanisms underlying the association between leptin levels and T2D.

scholarly journals Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1275
Author(s):  
Anca Cismaru ◽  
Deborah Rudin ◽  
Luisa Ibañez ◽  
Evangelia Liakoni ◽  
Nicolas Bonadies ◽  
...  
Keyword(s):  
Association Study ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Underlying Mechanism ◽  
Chromosome 9 ◽  
Genome Wide Association ◽  
Association Analyses ◽  
Genome Wide ◽  
Risk Patients ◽  
European Populations

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

scholarly journals Genome-Wide Association Study Highlights APOH as a Novel Locus for Lipoprotein(a) Levels

2020 ◽  
Author(s):  
Mary Hoekstra ◽  
Hao Yu Chen ◽  
Jian Rong ◽  
Line Dufresne ◽  
Jie Yao ◽  
...  
Keyword(s):  
Association Study ◽  
Large Scale ◽  
Genome Wide Association Study ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
European Ancestry ◽  
Linear Regression Models ◽  
Lipoprotein A ◽  
Genome Wide ◽  
A Genome

Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the LPA locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance (P ≤5×10 -8 ). In addition to validating previous associations at LPA , APOE , and CETP , we identified a novel variant at the APOH locus, encoding β2GPI (beta2-glycoprotein I). The APOH variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047–0.081]; P =2.8×10 -13 ) and demonstrated a stronger effect after adjustment for variation at the LPA locus (β [95% CI] [ln nmol/L], 0.089 [0.076–0.10]; P =3.8×10 -42 ). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044–0.28]; P =0.0071). Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified APOH as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.

scholarly journals Genome-wide meta-analysis identifies genetic locus on chromosome 9 associated with Modic changes

2019 ◽  
Vol 56 (7) ◽  
pp. 420-426 ◽  
Author(s):  
Maxim Freidin ◽  
Minna Kraatari ◽  
Sini Skarp ◽  
Juhani Määttä ◽  
Johannes Kettunen ◽  
...  
Keyword(s):  
Genetic Locus ◽  
Lumbar Disc ◽  
Meta Analysis ◽  
Chromosome 9 ◽  
Lumbar Disc Degeneration ◽  
Association Analyses ◽  
Bone Marrow Signal ◽  
Genome Wide ◽  
A Genome ◽  
Lumbar Mri

BackgroundLow back pain (LBP) is a common disabling condition. Lumbar disc degeneration (LDD) may be a contributing factor for LBP. Modic change (MC), a distinct phenotype of LDD, is presented as a pathological bone marrow signal change adjacent to vertebral endplate on MRI. It is strongly associated with LBP and has heritability around 30%. Our objective was to identify genetic loci associated with MC using a genome-wide meta-analysis.MethodsPresence of MC was evaluated in lumbar MRI in the Northern Finland Birth Cohort 1966 (n=1182) and TwinsUK (n=647). Genome-wide association analyses were carried out using linear regression model. Inverse-variance weighting approach was used in the meta-analysis.ResultsA locus associated with MC (p<5e-8) was found on chromosome 9 with the lead SNP rs1934268 in an intron of the PTPRD gene. It is located in the binding region of BCL11A, SPI1 and PBX3 transcription factors. The SNP was nominally associated with LBP in TwinsUK (p=0.001) but not associated in the UK Biobank (p=0.914). Suggestive signals (p<1e-5) were identified near XKR4, SCIN, MGMT, DLG2, ZNF184 and OPRK1.ConclusionPTPRD is a novel candidate gene for MC that may act via the development of cartilage or nervous system; further work is needed to define the mechanisms underlying the pathways leading to development of MC. This is the first genome-wide meta-analysis of MC, and the results pave the way for further studies on the genetic factors underlying the various features of spine degeneration and LBP.

scholarly journals A meta-analysis of genome-wide association studies for average daily gain and lean meat percentage in two Duroc pig populations

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shenping Zhou ◽  
Rongrong Ding ◽  
Fanming Meng ◽  
Xingwang Wang ◽  
Zhanwei Zhuang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Growth And Development ◽  
Genetic Architecture ◽  
Association Studies ◽  
Meta Analysis ◽  
Average Daily Gain ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Daily Gain

Abstract Background Average daily gain (ADG) and lean meat percentage (LMP) are the main production performance indicators of pigs. Nevertheless, the genetic architecture of ADG and LMP is still elusive. Here, we conducted genome-wide association studies (GWAS) and meta-analysis for ADG and LMP in 3770 American and 2090 Canadian Duroc pigs. Results In the American Duroc pigs, one novel pleiotropic quantitative trait locus (QTL) on Sus scrofa chromosome 1 (SSC1) was identified to be associated with ADG and LMP, which spans 2.53 Mb (from 159.66 to 162.19 Mb). In the Canadian Duroc pigs, two novel QTLs on SSC1 were detected for LMP, which were situated in 3.86 Mb (from 157.99 to 161.85 Mb) and 555 kb (from 37.63 to 38.19 Mb) regions. The meta-analysis identified ten and 20 additional SNPs for ADG and LMP, respectively. Finally, four genes (PHLPP1, STC1, DYRK1B, and PIK3C2A) were detected to be associated with ADG and/or LMP. Further bioinformatics analysis showed that the candidate genes for ADG are mainly involved in bone growth and development, whereas the candidate genes for LMP mainly participated in adipose tissue and muscle tissue growth and development. Conclusions We performed GWAS and meta-analysis for ADG and LMP based on a large sample size consisting of two Duroc pig populations. One pleiotropic QTL that shared a 2.19 Mb haplotype block from 159.66 to 161.85 Mb on SSC1 was found to affect ADG and LMP in the two Duroc pig populations. Furthermore, the combination of single-population and meta-analysis of GWAS improved the efficiency of detecting additional SNPs for the analyzed traits. Our results provide new insights into the genetic architecture of ADG and LMP traits in pigs. Moreover, some significant SNPs associated with ADG and/or LMP in this study may be useful for marker-assisted selection in pig breeding.

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