Meta-analysis Of Genetic Association Studies Research Articles

Comprehensive analysis of genes associated with migraine in the Indian population: a meta-analysis of genetic association studies with trial sequential analysis

Migraine is a complex disorder with multigenic inheritance and is characterized by the cardinal symptom of unilateral headache. Many genes are responsible for increasing the susceptibility of disease within different populations. Therefore, our primary aim in this review was to catalog the many genes that have been studied in India and after collecting the necessary information, we calculated a more precise risk relationship between an identified variation and migraine. The gene and its associated risk variant were discovered in the Indian population using a PRISMA-based systematic literature review guideline from online databases such as PubMed & Google Scholar. We constructed pooled odds ratios with 95% confidence intervals using multiple genetic models. Also, we looked for heterogeneity using Cochran's Q Test and the I2 statistic. Publication bias was analyzed using Begg's and Egger's tests. A p-value less than 0.05 was judged to be statistically significant for all tests. After a critical analysis, a total of 24 studies explored about 21 genes with 31 variants out of which only nine genes have been studied more than two times in the Indian population and thus were found eligible for the meta-analysis. It has been found, that the ACE-DD variant (allele model: OR: 1.37 [1.11–1.69], I2 = 0%/ fixed model), ESR1-PvuII (allele model: OR: 1.47 [1.24–1.74], I2 = 0%/ fixed model) significantly increases the risk of migraine in Indian population. Also, a protective role of the LRP1-rs11172113variant was observed for both migraine and its clinical subtype i.e., MA (allelic model: OR of 0.65 [0.50–0.83] I2 = 44% and allele: OR: 0.54 [0.37–0.78], I2 = 52%) respectively. Overall, the results of this meta-analysis indicated that the ACE-DD variant and the ESR1-PvuII were associated with an increased risk of migraine in the Indian community, while the LRP1-rs11172113 variant was associated with protection from migraine in this population.

Toll-like receptor 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer: a meta-analysis of genetic association studies

BackgroundGastric cancer has a complex aetiology including genetic factors. Individual case-control studies of toll like receptor (TLR) 9 (-1237 T/C, -1486 T/C) polymorphisms in the gastric cancer risk were available, and they showed variation in the findings. Therefore, we performed a meta-analysis to synthesize the evidence on the association between polymorphisms of TLR 9 (-1237 T/C, -1486 T/C) and the risk of gastric cancer using data from eligible studies.MethodsThis study followed the PRISMA 2020 Checklist. Studies were searched in health-related databases. The methodological quality of studies was evaluated with the use of Newcastle-Ottawa Scale criteria. The summary odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and the risk of gastric cancer using five genetic models. Stratification was done by ethnic groups. For the robustness of the analysis, a leave-one-out meta-analysis was performed.ResultsEight case-control studies with 3,644 participants (1914 cases, 1730 controls) were conducted across six countries. Half of the studies were conducted in China. In the NOS methodological quality assessment, only three studies received a high-quality rating (i.e., a score of ≥ 7). TLR 9 (-1486 T/C) polymorphism and the risk of gastric cancer were assessed in six studies, four of Asian ethnicity and two of non-Asian. Under the dominant model, only in the Asian ethnic group showed a marginally and significantly increased risk of gastric cancer (overall: OR = 1.22, 95%CI = 0.90–1.67, I2 = 56%; Asian: OR = 1.24, 95%CI = 1.00-1.54, I2 = 0%, non-Asian: OR = 1.25, 95%CI = 0.38–4.09, I2 = 89%). Under the recessive model in the absence of heterogeneity, only the Asian group had a significantly higher risk of developing gastric cancer (overall: OR = 1.4, 95% CI = 0.74–2.64, I2 = 85%; Asian: OR: 1.41, 95% CI = 1.07–1.86, I2 = 0%, non-Asian: OR = 1.18, 95% CI = 0.12–11.76, I2 = 97%). Under the heterozygous model, there was no significant association with the risk of gastric cancer overall or among any ethnic subgroup. Under the homozygous model in the absence of heterogeneity, only the Asian group had a significantly higher risk of gastric cancer (overall, OR = 1.47, 95% CI = 0.76–2.86, I2 = 82%; Asian: OR = 1.54, 95% CI = 1.13–2.1, I2 = 0%; non-Asian: OR = 1.19, 95% CI = 0.1-14.33, I2 = 96%). Under the allele model, a significantly increased risk of gastric cancer was observed only in the Asian group (overall: OR = 1.23, 95% CI = 0.89–1.71, I2 = 84%; Asian: OR = 1.22, 95% CI = 1.05–1.41, I2 = 0%; non-Asian: OR = 1.24, 95% CI = 0.34–4.59, I2 = 97%). Four studies investigated the association between TLR 9 (-1237 T/C) polymorphism and the risk of developing gastric cancer. Under any of the five genetic models, there was no association between TLR 9 (-1237 T/C) and the development of gastric cancer in overall or in any ethnic subgroup. Sensitivity analysis revealed that the effect was unstable. With a small number of studies with a small number of participants, we addressed the issue of insufficient power for drawing conclusions.ConclusionsThe findings suggested that TLR9 (-1486 T/C) may play a role in the risk of gastric cancer specific to the Asian ethnic group. To substantiate the findings on the association between these two polymorphisms (TLR9 -1237 T/C, -1486 T/C) and the risk of gastric cancer, future well-designed case-control studies with a sufficient number of participants in multi-ethnic groups are recommended.

A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.

Many homeostatic genes are thought to play a role in the susceptibility to migraine, making it a highly complex neurovascular disease. In this meta-analysis, our primary objective was to evaluate whether or not MTHFR variants (such as C677T and A1289C) and ACE I/D were associated with an increased risk of migraine. Using a PRISMA-based systematic literature-review guideline, internet sources such as PubMed and Google Scholar were searched to identify the genes of interest and migraine risk. To pool the data, odds ratios with 95% confidence intervals were calculated utilizing different genetic models. Cochran's Q Test and I2 statistics were used to access heterogeneity, while Begg's and Egger's tests were used to identify publication bias. All tests were two-sided, and a p-value of < 0.05 was regarded as statistically significant. The present meta-analysis observed that the C677T variant is significantly associated with the increased risk of migraine (allele model: OR:1.19, CI [1.07-1.33], I2 = 78%) and its clinical subtype i.e., MA (allele model: OR: 1.26, CI [1.09-1.45], I2 = 80%) in the overall population. Concerning the ACE- I/D, it significantly increased the risk of overall migraine and both clinical subtypes after utilizing the dominant genetic models (OR: 1.14, CI [1.01-1.29], I2% = 32). Concerning the MTHFR A1289C, only the codominant model (HR vs HT) and recessive model significantly increased the risk of overall migraine. Therefore, the findings of the present meta-analysis showed that MTHFR-C677T is an important risk factor for migraine and its clinical subtype.

The role of NLRP3 and CARD8 polymorphisms in the risk of rheumatoid arthritis: A meta-analysis of genetic association studies.

To investigate the potential associations between rheumatoid arthritis (RA) and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) rs35829419, rs10754558, s4612666, and caspase recruitment domain family member 8 (CARD8) rs2043211 polymorphisms. Relevant papers were searched for in MEDLINE, Embase, and Web of Science. Allele contrast, recessive, dominant, and homozygote contrast models were used to investigate the relationship between the NLRP3 rs35829419, rs10754558, and s4612666, and CARD8 rs2043211 polymorphisms and RA. This review was registered with PROSPERO (CRD42023451231). The meta-analysis included 11 comparative studies comprising 3789 patients with RA and 3956 controls. No significant association was found between NLRP3 rs35829419 C allele and RA in Europeans, Arabs, or Latinos. The NLRP3 rs10754558 G allele was not associated with RA in the Asian or Arab populations. However, a single study in Latin America discovered a link between RA and the NLRP3 rs10754558 G allele. The NLRP3 rs4612666 T allele was not associated with RA, according to the meta-analysis. When ethnicity was stratified, there was no association between the NLRP3 rs4612666 T allele and RA, except for a single study that found an association among Arabs. The CARD8 rs2043211 T allele did not seem to be associated with RA. According to an ethnic stratification study, the CARD8 rs2043211 T allele did not appear to be associated with RA in Europeans, Arabs, or Latinos. The meta-analysis indicated that the NLRP3 rs35829419, rs10754558, and s4612666 polymorphisms, as well as the CARD8 rs2043211 polymorphism, were not linked to RA susceptibility.

Systemic lupus erythematosus and toll-like receptor 9 polymorphisms: A meta-analysis of genetic association studies.

This study aimed to examine whether polymorphisms in toll-like receptor 9 (TLR9) contribute to vulnerability to systemic lupus erythematosus (SLE). We searched the MEDLINE, Embase, and Web of Science databases for relevant articles. We conducted a meta-analysis to examine the association between the TLR9 rs187084, rs352139, rs352140, and rs5743836 polymorphisms and SLE risk. A total of 5447 patients with SLE and 6588 control participants across 26 trials from 24 articles were included. The TLR9 rs187084 T allele was significantly associated with SLE (odds ratio, 1.146; 95% confidence interval, 1.033-1.273; p = 0.010). In a meta-analysis, the TLR9 rs187084 T allele was associated with SLE in the Asian population but not in the Arab population, demonstrating the existence of ethnicity-specific effects. Using homozygote contrast and recessive models, the researchers also found that the TLR9 rs187084 T/C polymorphism was associated with SLE. The TLR9 rs352139 G allele was not associated with SLE in this meta-analysis. After accounting for ethnic differences, we found that the TLR9 rs352139 G allele was not associated with SLE in Asians and Arabs. Furthermore, homozygote contrast and dominant models found no association between the TLR9 rs352139 G/A polymorphism and SLE. TLR9 polymorphisms at rs352140 and rs5743836 were not associated with an increased risk of SLE in any genetic prediction model, including people of Asian, European, or Latin American ancestry. SLE susceptibility is associated with the TLR9 rs187084 polymorphism in the Asian population and the rs187084, rs352139, rs352140, and rs5743836 polymorphisms in the Asian, European, and Latin American populations, respectively.

A web-based information system for cumulative and recursive cumulative meta-analysis of genetic association studies

Cumulative meta-analysis follows a methodical rather than a statistical approach, to show evolutions over time. Cumulative meta-analysis includes repeated meta-analyses over time of newly published studies on the research question. Thus, a meta-analysis is conducted each time a new study is published, and the pooled estimates and confidence intervals from all the meta-analyses are graphically displayed in chronological sequence. In this way, retrospectively it is possible to determine the point in time from which a statistically significant effect becomes apparent. Recursive cumulative meta-analyses find changes in the common estimator by performing a meta-analysis of the chronologically arranged papers at the conclusion of each year. The strong assumption of a delay bias (“lag time bias”) is supported by an ever-declining effect. Although there are a number of software programs that perform meta-analysis, none of them have been expressly created for genetic association studies, and using them frequently necessitates advanced programming or scripting skills. Of course, they are unable to do cumulative and recursive cumulative meta-analyses. We developed Genetical Evidence SYNthesis (GESYN), a web-application for cumulative and recursive cumulative meta-analysis of Genetic association studies (GAS). GESYN can be run in an environment that is easy to use.11The Web-application is available free of charge after registration at https://biomath.med.uth.gr/.

Aldehyde dehydrogenase 2 rs671 polymorphism and multiple diseases: protocol for a quantitative umbrella review of meta-analyses

BackgroundThe mutant allele (*2) of aldehyde dehydrogenase type 2 (ALDH2) caused by a single nucleotide variant (rs671) inhibits enzymatic activity and is associated with multiple diseases. In recent years, an explosive number of original studies and meta-analyses have been conducted to examine the associations of ALDH2 rs671 polymorphism with diseases. Due to conflicting results, the overall associations of ALDH2 rs671 polymorphism and multiple diseases remain unclear.MethodsA quantitative umbrella review will be conducted on meta-analyses of genetic association studies to examine the pleiotropic effects of ALDH2 rs671, mainly including cardio-cerebral vascular disease, diabetes mellitus, cancer, neurodegenerative disease, and alcohol-induced medical disease. A search of relevant literature according to comprehensive search strategies will be performed on studies published before July 1st, 2022 in PubMed, MEDLINE Ovid, Embase, Cochrane Database of Systematic Reviews, and Web of Science. Study selection, data extraction, methodology quality assessment, and strength of evidence assessment will be conducted by two reviewers independently and in duplicate. Included meta-analyses will be grouped by outcomes. Data conflicts and overlap between meta-analyses will be managed through updated standardized and customized methods including the calculation of CCA for study selection reference, application of Doi plots to assess small-study effects and others. Evidence from included meta-analyses will be quantitatively synthesized by overlap-corrected analyses and meta-analysis using primary studies.DiscussionThis umbrella review is expected to generate systematic evidence on the association between ALDH2 rs671 and diseases. Specific approaches were developed to address key challenges in conducting an umbrella review, including assessment tools of methodology and evidence quality of meta-analyses, methods to manage overlap between meta-analyses, a “stop-light” plot to summarize key findings. These approaches provide applicable methods for future umbrella reviews of meta-analyses on genetic association studies.Trial registrationCRD42021223812

Toll-like receptor 9 and 4 gene polymorphisms in susceptibility and severity of malaria: a meta-analysis of genetic association studies

BackgroundMalaria is still a major public health problem in sub-Saharan Africa and South-east Asia. The clinical presentations of malaria infection vary from a mild febrile illness to life-threatening severe malaria. Toll like receptors (TLRs) are postulated to be involved in the innate immune responses to malaria. Individual studies showed inconclusive findings. This study aimed to assess the role of TLR4 (D299G, T399I) and TLR9 (T1237C, T1486C) in severity or susceptibility of malaria by meta-analysis of data from eligible studies.MethodsRelevant case–control studies that assessed the association between TLR 4/9 and malaria either in susceptibility or progression were searched in health-related electronic databases. Quality of included studies was evaluated with Newcastle–Ottawa scale. Pooled analyses for specific genetic polymorphisms were done under five genetic models. Stratified analysis was done by age and geographical region (Asian countries vs non-Asian countries).ResultsEleven studies (2716 cases and 2376 controls) from nine endemic countries were identified. Five studies (45.4%) obtained high score in quality assessment. Overall, a significant association between TLR9 (T1486C) and severity of malaria is observed in allele model (OR: 1.26, 95% CI: 1.08–1.48, I2 = 0%) or homozygous model (OR: 1.55, 95% CI: 1.08–2.28, I2 = 0%). For TLR9 (T1237C), a significant association with severity of malaria is observed in in heterozygous model (OR:1.89, 95% CI: 1.11–3.22, I2 = 75%). On stratifications, TLR9 (T1486C) is only significantly associated with a subgroup of children of non-Asian countries under allele model (OR: 1.25, 95% CI: 1.02–1.38), while 1237 is with a subgroup of adults from Asian countries under heterozygous model (OR: 2.0, 95% CI: 1.09–3.64, I2 = 39%). Regarding the susceptibility to malaria, TLR9 (T1237C) is significantly associated only with the children group under recessive model (OR: 2.21, 95% CI: 1.06–4.57, I2=85%) and homozygous model (OR: 1.49, 95% CI: 1.09–2.0, I2 = 0%). For TLR4 (D299G, T399I), none is significantly associated with either severity of malaria or susceptibility to malaria under any genetic models.ConclusionsThe findings suggest that TLR 9 (T1486C and T1237C) seems to influence the progression of malaria, under certain genetic models and in specific age group of people from specific geographical region. TLR 9 (T1237C) also plays a role in susceptibility to malaria under certain genetic models and only with children of non-Asian countries. To substantiate these, future well designed studies with larger samples across endemic countries are needed.

Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse

Introduction and hypothesisFamily and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations.MethodsUpdating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria.ResultsWe screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the ESR1 gene (OR 0.67 95% CI 0.46–0.98, I2 = 0.0%, Venice rating BAB), rs12589592 at the FBLN5 gene (OR 1.46 95% CI 1.11–1.82, I2 = 36.3%, Venice rating BBB), rs484389 in the PGR gene (OR 0.61 95% CI 0.39–0.96, I2 = 32.4%, Venice rating CBB), and rs1800012 at the COL1A1 gene (OR 0.80 95% CI 0.66–0.96, I2 = 0.0%, Venice rating BAB). Further credible novel variants have also been recently identified in genome-wide association studies.ConclusionThe genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice.

Genetic factors contributing to skeletal class III malocclusion: a systematic review and meta-analysis.

The present systematic review aims to report and critically assess the findings of the available scientific evidence from genetic association studies examining the genetic variants underlying skeletal class III malocclusion and its sub-phenotypes. A pre-piloted protocol was registered and followed. The PubMed, Scopus, WOS, Cochrane Library, Gray Open literature, and CADTH databases were explored for genetic association studies following PICOS-based selection criteria. The research was reported in accordance with PRISMA statement and HuGE guidelines. The Q-genie tool was applied to assess the quality of genetic studies. Meta-analysis of genetic association studies was done by means of Meta-Genyo tool. A total of 8258 articles were retrieved, of which 22 were selected for in-depth analysis. Most of the studies did not differentiate between sub-phenotypes, and the cohorts were heterogeneous regarding ethnicity. Four to five principal components of class III malocclusion explained the phenotypic variation, and gene variants at MYO1H(rs10850110), BMP3(rs1390319), GHR (rs2973015,rs6184, rs2973015), FGF7(rs372127537), FGF10(rs593307), and SNAI3(rs4287555) (p < .05) explained most of the variation across the studies, associated to vertical, horizontal, or combined skeletal discrepancies. Meta-analysis results identified a statistically significant association between risk of class III malocclusion of A allele of the FBN3 rs7351083 [OR 2.13; 95% CI 1.1-4.1; p 0.02; recessive model]. Skeletal class III is a polygenic trait substantially modulated by ethnicity. A multicentric approach should be considered in future studies to increase sample sizes, applying multivariate analysis such as PCA and cluster analysis to characterize existing sub-phenotypes warranting a deeper analysis of genetic variants contributing to skeletal class III craniofacial disharmony. Grasping the underlying mechanisms of this pathology is critical for a fuller understanding of its etiology, allowing generation of preventive strategies, new individualized therapeutic approaches and more accurate treatment planification strategies.

PPARG (Pro12Ala) genetic variant and risk of T2DM: a systematic review and meta-analysis

Type 2 diabetes mellitus (T2DM) is a complex disease caused by the interaction between genetic and environmental factors. A growing number of evidence suggests that the peroxisome proliferator-activated receptor gamma (PPARG) gene plays a major role in T2DM development. Meta-analysis of genetic association studies is an efficient tool to gain a better understanding of multifactorial diseases and potentially to provide valuable insights into gene-disease interactions. The present study was focused on assessing the association between Pro12Ala variation in the PPARG and T2DM risk through a comprehensive meta-analysis. We searched PubMed, WoS, Embase, Scopus and ProQuest from 1990 to 2017. The fixed-effect or random-effect model was used to evaluate the pooled odds ratios (ORs) and 95% confidence intervals (CIs) depending on the heterogeneity among studies. The sources of heterogeneity and publication bias among the included studies were assessed using I2 statistics and Egger's tests. A total of 73 studies, involving 62,250 cases and 69,613 controls were included. The results showed that the minor allele (G) of the rs1801282 variant was associated with the decreased risk of T2DM under different genetic models. Moreover, the protective effect of minor allele was detected to be significantly more in some ethnicities including the European (18%), East Asian (20%), and South East Asian (18%). And the reduction of T2DM risk in Ala12 carriers was stronger in individuals from North Europe rather than Central and South Europe. Our findings indicated that the rs1801282 variant may contribute to decrease of T2DM susceptibility in different ancestries.

The genetic map of diabetic nephropathy: evidence from a systematic review and meta-analysis of genetic association studies.

Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (ORG). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger’s test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. ACACB, angiotensin I-converting enzyme (ACE), ADIPOQ, AGT, AGTR1, AKR1B1, APOC1, APOE, ATP1B2, ATP2A3, CARS, CCR5, CGNL1, Carnosine dipeptidase 1 (CNDP1), CYGB-PRCD, EDN1, Engulfment and cell motility 1 (ELMO1), ENPP1, EPO, FLT4, FTO, GLO1, HMGA2, IGF2/INS/TH cluster, interleukin 1B (IL1B), IL8, IL10, KCNQ1, KNG, LOC101927627, Methylenetetrahydrofolate reductase, nitric oxide synthase 3 (NOS3), SET domain containing seven, histone lysine methyltransferase (SETD7), Sirtuin 1 (SIRT1), SLC2A1, SLC2A2, SLC12A3, SLC19A3, TCF7L2, TGFB1, TIMP1, TTC39C, UNC13B, VEGFA, WTAPP1, WWC1 as well as XYLT1 and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.

Association of candidate gene polymorphisms with diabetic retinopathy in Chinese patients with type 2 diabetes.

To investigate the association between a set of six candidate genes and the risk of diabetic retinopathy (DR) in an urban community cohort of Chinese patients with type 2 diabetes mellitus (T2DM). A population-based cross-sectional study. The diabetic subjects were recruited from an urban community in Beijing and categorized into groups of proliferative diabetic retinopathy (PDR), non-proliferative diabetic retinopathy (NPDR), or diabetic without any retinopathy (DWR) based on the fundus photography and duration of diabetes. Six candidate genes, including advanced glycation end product specific receptor (AGER), aldose reductase (AKR1B1), inducible nitric oxide synthase (iNOS), pigment epithelium derived factor (PEDF), tumor necrosis factor-alpha (TNF-α), and paraoxonase 1 (PON1), were chosen based on Meta-analysis of genetic association studies for DR and biochemical pathways implicated in DR progression. The allele and genotype distribution of 21 functional single-nucleotide polymorphisms (SNPs) in those 6 candidate genes were investigated using MassARRAY genotyping system. Among 1461 diabetic patients recruited from community, 569 were selected in following genotyping analysis, including 97 patients with PDR, 217 with NPDR, and 255 with DWR. For the promoter variant rs1051993 in AGER gene, the distribution of allele and genotype in PDR group differed from that in DWR group (allele: P=0.011; genotype: P=0.01). Compared with DWR, patients with PDR had lower frequencies of heterozygous genotype GT (9.8% for DWR, 1% for PDR, OR: 0.10, 95%CI: 0.01-0.72) and minor allele T (4.9% for DWR, 0.5% for PDR, OR: 0.10, 95%CI: 0.01-0.75). In multivariate model, the distribution of genotype for rs1051993 in PDR group was significantly different from that in DWR group (GT vs GG: OR: 0.07, 95%CI: 0.01-0.61, P<0.001). No association with DR was observed in other genotyped SNPs. The data suggest a significant association of the promoter variant rs1051993 in AGER gene with PDR in Chinese cohort with T2DM.

Loss-of-function mutations in the melanocortin-3 receptor gene confer risk for human obesity: A systematic review and meta-analysis.

The association between rare coding loss-of-function (LOF) mutations in the melanocortin receptor 3 (MC3R) gene and human obesity is controversial. To fill this gap of knowledge, we performed a systematic review and meta-analysis of genetic association studies in all ages and ethnicities. Two reviewers independently performed risk of bias assessment and extracted data. We searched Medline, Embase, Web of Science Core Collection, BIOSIS Preview, CINAHL, ProQuest Dissertations & Theses, and reference lists of relevant studies. All case-control, cross-sectional, prospective, and retrospective studies that evaluated prevalence of rare (less than 1% frequency) coding partial/complete LOF mutations in MC3R among individuals with obesity and normal weight were included. Our systematic search identified 1925 references relevant to the present review. Six studies were deemed eligible. Meta-analysis of 2969 individuals with obesity and 2572 with normal weight showed a positive association between rare heterozygous coding partial/complete LOF mutations in MC3R and obesity in children and adults of European, North African, and Asian ancestries (odds ratio=3.07; 95% CI, 1.48-7.00; P=4.2×10-3 ). Our data demonstrates that rare partial/complete LOF mutations in the coding region of MC3R confer three-time increased risk of obesity in humans, and implies that rare genetic variants with intermediate effects contribute to the missing heritability of obesity.

Field synopsis and systematic meta-analyses of genetic association studies in isolated dystonia

Background and objectivesDystonia is a genetically complex disease with both monogenic and polygenic causes. For the latter, numerous genetic associations studies have been performed with largely inconsistent results. The aim of this study was to perform a field synopsis including systematic meta-analyses of genetic association studies in isolated dystonia. MethodsFor the field synopsis we systematically screened and scrutinized the published literature using NCBI's PubMed database. For genetic variants with sufficient information in at least two independent datasets, random-effects meta-analyses were performed, including meta-analyses stratified by ethnic descent and dystonia subtypes. ResultsA total of 3575 articles were identified and scrutinized resulting in the inclusion of 42 independent publications allowing 134 meta-analyses on 45 variants across 17 genes. While our meta-analyses pinpointed several association signals with variants in TOR1A, DRD1, and ARSG, no single variant displayed compelling association with dystonia in the available data. ConclusionsOur study provides an up-to-date summary of the status of dystonia genetic association studies. Additional large-scale studies are needed to better understand the genetic causes of isolated dystonia.

Proper conditional analysis in the presence of missing data: Application to large scale meta-analysis of tobacco use phenotypes.

Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values. Existing methods for imputing missing summary association statistics and using imputed values in meta-analysis, approximate conditional analysis, or simple strategies such as complete case analysis all have theoretical limitations. Applying these approaches can bias genetic effect estimates and lead to seriously inflated type-I or type-II errors in conditional analysis, which is a critical tool for identifying independently associated variants. To address this challenge and complement imputation methods, we developed a method to combine summary statistics across participating studies and consistently estimate joint effects, even when the contributed summary statistics contain large amounts of missing values. Based on this estimator, we proposed a score statistic called PCBS (partial correlation based score statistic) for conditional analysis of single-variant and gene-level associations. Through extensive analysis of simulated and real data, we showed that the new method produces well-calibrated type-I errors and is substantially more powerful than existing approaches. We applied the proposed approach to one of the largest meta-analyses to date for the cigarettes-per-day phenotype. Using the new method, we identified multiple novel independently associated variants at known loci for tobacco use, which were otherwise missed by alternative methods. Together, the phenotypic variance explained by these variants was 1.1%, improving that of previously reported associations by 71%. These findings illustrate the extent of locus allelic heterogeneity and can help pinpoint causal variants.

A simulations approach for meta-analysis of genetic association studies based on additive genetic model

Meta-analysis of genetic association studies is being increasingly used to assess phenotypic differences between genotype groups. When the underlying genetic model is assumed to be dominant or recessive, assessing the phenotype differences based on summary statistics, reported for individual studies in a meta-analysis, is a valid strategy. However, when the genetic model is additive, a similar strategy based on summary statistics will lead to biased results. This fact about the additive model is one of the things that we establish in this paper, using simulations. The main goal of this paper is to present an alternate strategy for the additive model based on simulating data for the individual studies. We show that the alternate strategy is far superior to the strategy based on summary statistics.

Multivariate Methods for Meta-Analysis of Genetic Association Studies.

Multivariate meta-analysis of genetic association studies and genome-wide association studies has received a remarkable attention as it improves the precision of the analysis. Here, we review, summarize and present in a unified framework methods for multivariate meta-analysis of genetic association studies and genome-wide association studies. Starting with the statistical methods used for robust analysis and genetic model selection, we present in brief univariate methods for meta-analysis and we then scrutinize multivariate methodologies. Multivariate models of meta-analysis for a single gene-disease association studies, including models for haplotype association studies, multiple linked polymorphisms and multiple outcomes are discussed. The popular Mendelian randomization approach and special cases of meta-analysis addressing issues such as the assumption of the mode of inheritance, deviation from Hardy-Weinberg Equilibrium and gene-environment interactions are also presented. All available methods are enriched with practical applications and methodologies that could be developed in the future are discussed. Links for all available software implementing multivariate meta-analysis methods are also provided.

Collagen type-I A2 gene polymorphisms and susceptibility to intracranial aneurysms: a meta-analysis of genetic association studies

ABSTRACTBackground: The development, evolution and rupture of intracranial aneurysms are in part related to genetic factors. The role of collagen type-I a2 genetic polymorphisms has not been clarified yet.Material and methods: A meta-analysis was realized by means of a genotype model-fitting process (allele contrast, recessive, dominant, additive and co-dominant), and a model-free approach using the generalized odds ratio. The latter was assessed in association to the degree of dominance (h-index).Results: No statistically significant association was documented between EX28 G>C collagen type-I a2 variant and intracranial aneurysms (generalized odds ratio = 1.23, 95% confidence interval = 0.57, 2.63). Significant associations between INT46 T>G collagen type I a2 variant and intracranial aneurysms were documented in three models, the dominant [0.52 (0.38, 069)], the co-dominant [0.50 (0.32, 0.78)] and the allele contrast models [0.63 (0.49, 0.82)]. The generalized odds ratio was estimated to be as high as 1.94 (1.23, 3.06). The degree of dominance (h-index = −1.54) indicated that the TG genotype was characterized by lower risk of developing intracranial aneurysms compared to the TT genotype.Conclusions: The available literature data demonstrated that there is no association of collagen type-(2a) and intracranial aneurysms, through EX28 G>C (rs42524) polymorphism according to the model-fitting process and the model-free approach. Regarding the INT46 T>G (rs2621215) polymorphisms, the latter models indicated that there could be a protective effect of the G-allele against the development of intracranial aneurysms. However, the majority of studies are from East Asia, therefore the results are applicable primarily to that patient population.

Choice of genetic model on Meta-analysis of genetic association studies: introduction of genetic model-free approach for Bayesian analysis

Meta-analysis used for genetic association studies became popular among researchers, with the amount of published papers increased rapidly. In this paper, we will focus on the introduction on the selection of genetic models. Traditionally, methods used for Meta-analysis on genetic association studies was to calculate the statistics based on available genetic models which not only increasing the probability of false-positives but also making the interpretation of results more difficult. Hence, a critical step in the Meta-analysis of genetic association studies was to choose the appropriate inheritance model. The aim of this paper was to introduce the theory of Bayesian analysis regarding the genetic model-free approach, in performing the Meta-analysis for studies related to genetic associations.