Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis

AbstractChronic Kidney Disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. Previous genome-wide association study (GWAS) meta-analyses of CKD and eGFR or related phenotypes have identified a number of variants associated with kidney function, but these only explain a fraction of the variability in kidney phenotypes attributed to genetic components. To extend these studies, we analyzed data from the Nord-Trøndelag Health Study (HUNT), which is more densely imputed than previous studies, and performed a GWAS meta-analysis of eGFR with publicly available summary statistics, more than doubling the sample size of previous meta-analyses. We identified 147 loci (53 novel loci) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Moreover, genes at these loci show enriched expression in urogenital tissues and highlight gene sets known to play a role in kidney function. In addition, sex-stratified analysis identified three regions (prioritized genes: PPM1J, MCL1, and SLC47A1) with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD but improve detection only modestly compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

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

Scientific Reports ◽

10.1038/srep45040 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 51

Author(s):

Mathias Gorski ◽

Peter J. van der Most ◽

Alexander Teumer ◽

Audrey Y. Chu ◽

Man Li ◽

...

Keyword(s):

Kidney Function ◽

Kidney Development ◽

Association Studies ◽

Meta Analysis ◽

European Ancestry ◽

P Value ◽

Genome Wide Association Studies ◽

1000 Genomes ◽

Gene Sets ◽

Project Promise

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

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Phenotypic and Genotypic Associations Between Migraine and Lipoprotein Subtractions

Neurology ◽

10.1212/wnl.0000000000012919 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012919

Author(s):

Yanjun Guo ◽

Iyas Daghlas ◽

Padhraig Gormley ◽

Franco Giulianini ◽

Paul M Ridker ◽

...

Keyword(s):

Genetic Correlation ◽

Genetic Relationships ◽

Meta Analysis ◽

European Ancestry ◽

Health Study ◽

Lipoprotein Subfractions ◽

Genetic Components ◽

The Uk ◽

Summary Data

Background and Objective:To evaluate phenotypic and genetic relationships between migraine and lipoprotein subfractions.Methods:We evaluated phenotypic associations between migraine and 19 lipoprotein subfractions measures in the Women’s Genome Health Study (WGHS, N=22,788). We then investigated genetic relationships between these traits using summary statistics from the International Headache Genetics Consortium (IHGC) for migraine (Ncase=54,552, Ncontrol=297,970) and combined summary data for lipoprotein subfractions (N up to 47,713).Results:There was a significant phenotypic association (odds ratio=1.27 [95% confidence interval:1.12-1.44]) and a significant genetic correlation at 0.18 (P=0.001) between migraine and triglyceride-rich lipoproteins (TRLP) concentration but not for LDL or HDL subfractions. Mendelian randomization (MR) estimates were largely null implying that pleiotropy rather than causality underlies the genetic correlation between migraine and lipoprotein subfractions. Pleiotropy was further supported in cross-trait meta-analysis revealing significant shared signals at four loci (chr2p21 harboring THADA, chr5q13.3 harboring HMGCR, chr6q22.31 harboring HEY2, and chr7q11.23 harboring MLXIPL) between migraine and lipoprotein subfractions. Three of these loci were replicated for migraine (P<0.05) in a smaller sample from the UK Biobank. The shared signal at chr5q13.3 colocalized with expression of HMGCR, ANKDD1B, and COL4A3BP in multiple tissues.Conclusions:The current study supports the association between certain lipoprotein subfractions, especially for TRLP, and migraine in populations of European ancestry. The corresponding shared genetic components may be help identify potential targets for future migraine therapeutics.Classification of Evidence:This study provides Class I evidence that migraine is significantly associated with some lipoprotein subfractions.

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Genome-wide association study of treatment-resistance in depression and meta-analysis of three independent samples

The British Journal of Psychiatry ◽

10.1192/bjp.2018.256 ◽

2018 ◽

Vol 214 (1) ◽

pp. 36-41 ◽

Cited By ~ 13

Author(s):

Chiara Fabbri ◽

Siegfried Kasper ◽

Alexander Kautzky ◽

Lucie Bartova ◽

Markus Dold ◽

...

Keyword(s):

Genome Wide Association Study ◽

Meta Analysis ◽

Adenosine Monophosphate ◽

Research Support ◽

Antidepressant Treatments ◽

Advisory Boards ◽

Gene Sets ◽

Genome Wide ◽

A Genome ◽

Resistant Depression

BackgroundTreatment-resistant depression (TRD) is the most problematic outcome of depression in terms of functional impairment, suicidal thoughts and decline in physical health.AimsTo investigate the genetic predictors of TRD using a genome-wide approach to contribute to the development of precision medicine.MethodA sample recruited by the European Group for the Study of Resistant Depression (GSRD) including 1148 patients with major depressive disorder (MDD) was characterised for the occurrence of TRD (lack of response to at least two adequate antidepressant treatments) and genotyped using the Infinium PsychArray. Three clinically relevant patient groups were considered: TRD, responders and non-responders to the first antidepressant trial, thus outcomes were based on comparisons of these groups. Genetic analyses were performed at the variant, gene and gene-set (i.e. functionally related genes) level. Additive regression models of the outcomes and relevant covariates were used in the GSRD participants and in a fixed-effect meta-analysis performed between GSRD, STAR*D (n = 1316) and GENDEP (n = 761) participants.ResultsNo individual polymorphism or gene was associated with TRD, although some suggestive signals showed enrichment in cytoskeleton regulation, transcription modulation and calcium signalling. Two gene sets (GO:0043949 and GO:0000183) were associated with TRD versus response and TRD versus response and non-response to the first treatment in the GSRD participants and in the meta-analysis, respectively (corrected P = 0.030 and P = 0.027).ConclusionsThe identified gene sets are involved in cyclic adenosine monophosphate mediated signal and chromatin silencing, two processes previously implicated in antidepressant action. They represent possible biomarkers to implement personalised antidepressant treatments and targets for new antidepressants.Declaration of interestD.S. has received grant/research support from GlaxoSmithKline and Lundbeck; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen and Lundbeck. S.M. has been a consultant or served on advisory boards for: AstraZeneca, Bristol-Myers Squibb, Forest, Johnson & Johnson, Leo, Lundbeck, Medelink, Neurim, Pierre Fabre, Richter. S.K. has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, Pierre Fabre, Janssen and Neuraxpharm. J.Z. has received grant/research support from Lundbeck, Servier, Brainsway and Pfizer, has served as a consultant or on advisory boards for Servier, Pfizer, Abbott, Lilly, Actelion, AstraZeneca and Roche and has served on speakers' bureaus for Lundbeck, Roch, Lilly, Servier, Pfizer and Abbott. J.M. is a member of the Board of the Lundbeck International Neuroscience Foundation and of Advisory Board of Servier. A.S. is or has been consultant/speaker for: Abbott, AbbVie, Angelini, Astra Zeneca, Clinical Data, Boehringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi and Servier. C.M.L. receives research support from RGA UK Services Limited.

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Influence ofDPYDGenetic Polymorphisms on 5-Fluorouracil Toxicities in Patients with Colorectal Cancer: A Meta-Analysis

Gastroenterology Research and Practice ◽

10.1155/2014/827989 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 9

Author(s):

Qiang Li ◽

Ying Liu ◽

Hong-Mei Zhang ◽

Yin-Peng Huang ◽

Tian-Yi Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Polymorphisms ◽

Web Of Science ◽

Meta Analysis ◽

Dihydropyrimidine Dehydrogenase ◽

Cochrane Library ◽

Inclusion Criteria ◽

Meta Analyses ◽

The Cochrane Library ◽

Stratified Analysis

Our meta-analysis aggregated existing results from relevant studies to comprehensively investigate the correlations between genetic polymorphisms in dihydropyrimidine dehydrogenase (DPYD) gene and 5-fluorouracil (5-FU) toxicities in patients with colorectal cancer (CRC). The MEDLINE (1966∼2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980∼2013), CINAHL (1982∼2013), Web of Science (1945∼2013), and the Chinese Biomedical Database (CBM) (1982∼2013) were searched without language restrictions. Meta-analyses were conducted with the use of STATA software (Version 12.0, Stata Corporation, College Station, TX, USA). Seven clinical cohort studies with a total of 946 CRC patients met our inclusion criteria, and NOS scores of each of the included studies were ≥5. Our findings showed thatDPYDgenetic polymorphisms were significantly correlated with high incidences of 5-FU-related toxicity in CRC patients. SNP-stratified analysis indicated that there were remarkable connections of IVS14+1G>A, 464T>A, and 2194G>A polymorphisms with the incidence of marrow suppression in CRC patients receiving 5-FU chemotherapy. Furthermore, we found that IVS14+1G>A, 496A>G, and 2194G>A polymorphisms were correlated with the incidence of gastrointestinal reaction. Ethnicity-stratified analysis also revealed thatDPYDgenetic polymorphisms might contribute to the development of marrow suppression and gastrointestinal reaction among Asians, but not among Caucasians. The present meta-analysis suggests thatDPYDgenetic polymorphisms may be correlated with the incidence of 5-FU-related toxicity in CRC patients.

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Polygenic Risk Scores Augment Stroke Subtyping

Neurology Genetics ◽

10.1212/nxg.0000000000000560 ◽

2021 ◽

Vol 7 (2) ◽

pp. e560

Author(s):

Jiang Li ◽

Durgesh P. Chaudhary ◽

Ayesha Khan ◽

Christoph Griessenauer ◽

David J. Carey ◽

...

Keyword(s):

Ischemic Stroke ◽

Genetic Correlation ◽

Genome Wide Association Study ◽

Low Frequency ◽

European Ancestry ◽

Risk Scores ◽

Polygenic Risk Score ◽

Large Artery ◽

Polygenic Risk ◽

Gene Sets

ObjectiveTo determine whether the polygenic risk score (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary health care system and to identify the PRS derived from gene sets of known biological pathways associated with IS.MethodsControls (n = 19,806/7,484, age ≥69/79 years) and cases (n = 1,184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors were identified by leveraging the Geisinger Electronic Health Record and chart review confirmation. All Geisinger MyCode patients with age ≥69/79 years and without any stroke-related diagnostic codes were included as low risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE (EUR) were calculated using the summary statistics of the genome-wide association study by linkage disequilibrium score regression. All PRS for any stroke (AS), any ischemic stroke (AIS), large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS) were constructed by PRSice-2.ResultsA moderate heritability (10%–20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Variation of all 5 PRS significantly explained some of the phenotypic variations of Geisinger IS, and the R2 increased by raising the cutoff for the age of controls. PRSLAS, PRSCES, and PRSSVS derived from low-frequency common variants provided the best fit for modeling (R2 = 0.015 for PRSLAS). Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRSLAS, PRSCES, and PRSSVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping.ConclusionsWe provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.

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Abstract P274: A meta-analysis of meta-analyses: Is "reverse Epi" OK or not?

Circulation ◽

10.1161/circ.129.suppl_1.p274 ◽

2014 ◽

Vol 129 (suppl_1) ◽

Author(s):

Ken Williams ◽

Allan D Sniderman

Keyword(s):

Observational Studies ◽

Meta Analysis ◽

Geometric Mean ◽

Point Estimate ◽

Risk Models ◽

Percentage Difference ◽

Chd Risk ◽

The Difference ◽

Meta Analyses ◽

Stratified Analysis

Introduction: Applications of observational risk models assuming “all else equal” to estimate the effect on risk of interventions expected to change the level of one or more independent variables have been criticized as “reverse Epi” since clinical trials provide better estimates of treatment effects. Hypothesis: The purpose of this analysis is to assess how reasonable it is to use “reverse Epi” to project the number of events avoided under different scenarios in which different markers are used for determining to whom to prescribe and how to target preventative treatment. We pursued this aim by comparing two different meta-analyses which compared HRs for apoB and non-HDL-C. One meta-analysis included 12 published observational studies. In 11 of these studies all subjects were at primary CHD risk. The other meta-analysis included 7 placebo-controlled statin trials (3 primary and 4 secondary). Methods: We calculated the reciprocal of each observational study’s HR per 1-SD increase (36 mg/dl for non-HDL-C and 27 mg/dl of apoB) to compare with each trials’ HR per 1-SD decrease; calculated the percentage difference (95% CI) in standard HRs for each report assuming a correlation between the two markers of 0.93 (calculated from NHANES 2005-2010 to be representative of adult US residents); and compared the resulting statistics using standard subgroup meta-analysis. Results: The overall geometric mean point estimate (95% CI) of the difference favoring apoB over non-HDL-C for all observational studies was 11.1% (7.7%, 14.4%) versus 5.4% (2.9%, 9.2%) for all 7 trials (p = 0.007). However these same point estimates are 9.5% (7.3%, 14.0%) versus 10.6% (7.3%, 14.0%) (p=0.714) when only primary studies or trials were included. The geometric mean treatment effect HR among the 4 secondary trials was 0.732 (0.689, 0.792) versus 0.599 (0.504, 0.714) among the 3 primary trials (p = 0.035). Conclusion: Meaningful differences between primary and secondary observational and interventional studies warrant stratified analysis. Among subjects at primary CHD risk, “reverse Epi” application of primary observational results may provide projections similar to those from applying primary trial results.

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O-116 Genetic association analyses identify links between pelvic prolapse (PP) and connective tissue biology, cardiovascular and reproductive health

Human Reproduction ◽

10.1093/humrep/deab126.025 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

N Pujol Gualdo ◽

K Läll ◽

M Lepamets ◽

R Arffman ◽

T Piltonen ◽

...

Keyword(s):

Genetic Variants ◽

Genome Wide Association Study ◽

Genome Wide Association ◽

European Ancestry ◽

Risk Scores ◽

Polygenic Risk ◽

Genome Wide ◽

Meta Analyses ◽

Personalized Risk

Abstract Study question Can genome-wide association analysis unravel the biological underpinnings of PP and facilitate personalized risk assessment via genetic risk scores construction? Summary answer We unravel novel links with urogenital development and vascular health in PP and present polygenic risk score as a tool to stratify PP risk. What is known already Prolapse is characterized by a descent of the pelvic organs into the vaginal cavity. PP affects around 40% of women after menopause and is the main indication for major gynecological surgery, having an important health, social and economic burden. Although the etiology and biological mechanisms underlying PP remain poorly understood, prior studies suggest genetic factors might play a role. Recently, a genome-wide association study (GWAS) identified seven genome-wide significant loci, located in or near genes involved in connective tissue metabolism and estrogen exposure in the etiology of PP. Study design, size, duration We conducted a three-stage case-control genome-wide association study. Firstly, in the discovery phase, we meta-analyzed Icelandic, UK Biobank and the FinnGen R3 datasets, comprising a total of 20118 cases and 427426 controls of European ancestry. For replication we used an independent dataset from Estonian Biobank (7968 cases and 118895 controls). Finally, we conducted a joint meta-analysis, containing 28086 cases and 546321 controls, which is the largest GWAS of PP to date. Participants/materials, setting, methods We performed functional annotation on genetic variants unraveled by GWAS and integrated these with expression quantitative trait loci and chromatin interaction data. In addition, we looked at enrichment of association signal on gene-set, tissue and cell type level and analyzed associations with other phenotypes both on genetic and phenotypic level. Colocalisation analyses were conducted to help pinpoint causal genes. We further constructed polygenic risk scores to explore options for personalized risk assessment and prevention. Main results and the role of chance In the discovery phase, we identified 18 genetic loci and 20 genetic variants significantly associated with POP (p < 5 × 10−8) and 75% of the variants show nominal significance association (p < 0.05) in the replication. Notably, the joint meta-analyses detected 20 genetic loci significantly associated with POP, from which 13 loci were novel. Novel genetic variants are located in or near genes involved in gestational duration and preterm birth (rs2687728 p = 2.19x10-9, EEFSEC), cardiovascular health and pregnancy success (rs1247943 p = 5.83x10-18, KLF13), endometriosis (rs12325192 p = 3.72x10-18, CRISPLD2), urogenital tract development (rs7126322, p = 4.35x10-15, WT1 and rs42400, p = 4.8x10-10, ADAMTS16) and regulation of the oxytocin receptor (rs2267372, p = 4.49x10-13, MAFF). Further analyses demonstrated that POP GWAS signals colocalise with several eQTLS (including EEFSEC, MAFF, KLF13, etc.), providing further evidence for mapping associated genes. Tissue and cell enrichment analyses underlined the role of the urogenital system, muscle cells, myocytes and adipocytes (p < 0.00001, FDR<0.05). Furthermore, genetic correlation analyses supported a shared genetic background with gastrointestinal disorders, joint and musculoskeletal disorders and cardiovascular disease. Polygenic risk scores analyses included a total of 125551 people in the target dataset, with 5379 prevalent patients and 2517 incident patients. Analyzing the best GRS as a quintile showed association with incident disease (Harrell c-statistic= 0.603, SD = 0.006). Limitations, reasons for caution This GWAS meta-analyses focused on European ancestry populations, which challenges the generalizability of GWAS findings to non-European populations. Moreover, this study included women with PP from population-based biobanks identified using the ICD-10 code N81, which limits analyses considering different disease stages and severity. Wider implications of the findings Our study provides genetic evidence to improve the current understanding of PP pathogenesis and serves as basis for further functional studies. Moreover, we provide a genetic tool for personalized risk stratification, which could help prevent PP development and improve the quality of a vast quantity of women. Trial registration number not applicable

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A meta-analysis of genome-wide association studies of asthma in Puerto Ricans

European Respiratory Journal ◽

10.1183/13993003.01505-2016 ◽

2017 ◽

Vol 49 (5) ◽

pp. 1601505 ◽

Cited By ~ 30

Author(s):

Qi Yan ◽

John Brehm ◽

Maria Pino-Yanes ◽

Erick Forno ◽

Jerome Lin ◽

...

Keyword(s):

Puerto Ricans ◽

Association Studies ◽

Meta Analysis ◽

Linkage Disequilibrium Block ◽

Genome Wide Association ◽

Health Study ◽

Genome Wide Association Studies ◽

Genome Wide ◽

The Usa ◽

Meta Analyses

Puerto Ricans are disproportionately affected with asthma in the USA. In this study, we aim to identify genetic variants that confer susceptibility to asthma in Puerto Ricans.We conducted a meta-analysis of genome-wide association studies (GWAS) of asthma in Puerto Ricans, including participants from: the Genetics of Asthma in Latino Americans (GALA) I-II, the Hartford–Puerto Rico Study and the Hispanic Community Health Study. Moreover, we examined whether susceptibility loci identified in previous meta-analyses of GWAS are associated with asthma in Puerto Ricans.The only locus to achieve genome-wide significance was chromosome 17q21, as evidenced by our top single nucleotide polymorphism (SNP), rs907092 (OR 0.71, p=1.2×10−12) at IKZF3. Similar to results in non-Puerto Ricans, SNPs in genes in the same linkage disequilibrium block as IKZF3 (e.g. ZPBP2, ORMDL3 and GSDMB) were significantly associated with asthma in Puerto Ricans. With regard to results from a meta-analysis in Europeans, we replicated findings for rs2305480 at GSDMB, but not for SNPs in any other genes. On the other hand, we replicated results from a meta-analysis of North American populations for SNPs at IL1RL1, TSLP and GSDMB but not for IL33.Our findings suggest that common variants on chromosome 17q21 have the greatest effects on asthma in Puerto Ricans.

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Recent shifts in the genomic ancestry of Mexican Americans may alter the genetic architecture of biomedical traits

eLife ◽

10.7554/elife.56029 ◽

2020 ◽

Vol 9 ◽

Author(s):

Melissa L Spear ◽

Alex Diaz-Papkovich ◽

Elad Ziv ◽

Joseph M Yracheta ◽

Simon Gravel ◽

...

Keyword(s):

Complex Traits ◽

Mexican Americans ◽

Genetic Architecture ◽

Genome Wide Association Study ◽

The United States ◽

European Ancestry ◽

Risk Scores ◽

Health Study ◽

Complex Interactions ◽

Hispanic Community

People in the Americas represent a diverse continuum of populations with varying degrees of admixture among African, European, and Amerindigenous ancestries. In the United States, populations with non-European ancestry remain understudied, and thus little is known about the genetic architecture of phenotypic variation in these populations. Using genotype data from the Hispanic Community Health Study/Study of Latinos, we find that Amerindigenous ancestry increased by an average of ~20% spanning 1940s-1990s in Mexican Americans. These patterns result from complex interactions between several population and cultural factors which shaped patterns of genetic variation and influenced the genetic architecture of complex traits in Mexican Americans. We show for height how polygenic risk scores based on summary statistics from a European-based genome-wide association study perform poorly in Mexican Americans. Our findings reveal temporal changes in population structure within Hispanics/Latinos that may influence biomedical traits, demonstrating a need to improve our understanding of admixed populations.

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The genome-wide supported CACNA1C gene polymorphisms and the risk of schizophrenia: an updated meta-analysis

10.21203/rs.2.24453/v2 ◽

2020 ◽

Author(s):

Yongping Liu ◽

Xue Wu ◽

Xi Xia ◽

Jun Yao ◽

Bao-jie Wang

Keyword(s):

Genome Wide Association Study ◽

Meta Analysis ◽

European Ancestry ◽

Bias Analysis ◽

Influence Model ◽

Asian Populations ◽

Model Study ◽

Genome Wide ◽

Meta Analyses ◽

European Populations

Abstract Background: The CACNA1C gene was defined as a risk gene for schizophrenia in a large genome-wide association study of European ancestry performed by the Psychiatric Genomics Consortium. Previous meta-analyses focused on the association between the CACNA1C gene rs1006737 and schizophrenia. The present study focused on whether there was a racial difference in the effect of the CACNA1C gene rs1006737 on schizophrenia. rs2007044 and rs4765905 were analyzed for their effect on the risk of schizophrenia. Methods: Pooled, subgroup, sensitivity, and publication bias analysis were conducted.Results: A total of 18 studies met the inclusion criteria, including fourteen rs1006737 studies (15,213 cases, 19,412 controls), three rs2007044 studies (6,007 cases, 6,518 controls), and two rs4765905 studies (2,435 cases, 2,639 controls). An allele model study also related rs2007044 and rs4765905 to schizophrenia. The overall meta-analysis for rs1006737, which included the allele contrast, dominant, recessive, codominance, and complete overdominance models, showed significant differences between rs1006737 and schizophrenia. However, the race-based subgroup analysis for rs1006737 found that the genotypes GG and GG + GA were only protective factors for schizophrenia in European populations. In contrast, the rs1006737 GA genotype only reduced the risk of schizophrenia in Asian populations. Conclusions: Rs1006737, rs2007044, and rs4765905 of the CACNA1C gene were associated with susceptibility to schizophrenia. However, the influence model for rs1006737 on schizophrenia in Asian and European populations demonstrated both similarities and differences between the two populations.

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