Multiple Genetic Variants Research Articles

A comprehensive and universal approach for embryo testing in patients with different genetic disorders.

Background In vitro fertilization (IVF) with preimplantation genetic testing (PGT) has markedly improved clinical pregnancy outcomes for carriers of gene mutations or chromosomal structural rearrangements by the selection of embryos free of disease‐causing genes and chromosome abnormalities. However, for detecting whole or segmental chromosome aneuploidies, gene variants or balanced chromosome rearrangements in the same embryo require separate procedures, and none of the existing detection platforms is universal for all patients with different genetic disorders.MethodsHere, we report a cost‐effective, family‐based haplotype phasing approach that can simultaneously evaluate multiple genetic variants, including monogenic disorders, aneuploidy, and balanced chromosome rearrangements in the same embryo with a single test. A total of 12 monogenic diseases carrier couples and either of them carried chromosomal rearrangements were enrolled simultaneously in this present study. Genome‐wide genotyping was performed with single‐nucleotide polymorphism (SNP)‐array, and aneuploidies were analyzed through SNP allele frequency and Log R ratio. Parental haplotypes were phased by an available genotype from a close relative, and the embryonic genome‐wide haplotypes were determined through family haplotype linkage analysis (FHLA). Disease‐causing genes and chromosomal rearrangements were detected by haplotypes located within the 2 Mb region covering the targeted genes or breakpoint regions.ResultsTwelve blastocysts were thawed, and then transferred into the uterus of female patients. Nine pregnancies had reached the second trimester and five healthy babies have been born. Fetus validation results, performed with the amniotic fluid or umbilical cord blood samples, were consistent with those at the blastocyst stage diagnosed by PGT.ConclusionsWe demonstrate that SNP‐based FHLA enables the accurate genetic detection of a wide spectrum of monogenic diseases and chromosome abnormalities in embryos, preventing the transfer of parental genetic abnormalities to the fetus. This method can be implemented as a universal platform for embryo testing in patients with different genetic disorders.

Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a “pseudo” QRS complex suggesting reduced inward current(s). Voltage clamp analysis of ICa showed no difference in the magnitude of current. Measurements of INa reveal a 60% reduction in INa density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of INa was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of INa due to a mutation in PKP2 coupled with and a gain of function in IK,ATP due to a mutation in ABCC9.

Polygenic risk of genes involved in the catecholamine and serotonin pathways for ADHD in children

It is general acknowledged that genes play a vital role in the etiology of attention deficit/hyperactivity disorder (ADHD). The relationship between the genes involved in catecholamine (dopamine, noradrenaline)/serotonin transmissions and ADHD has been widely described in medical literature. A pathway-based study was conducted in this study to test the association of gene-gene interaction and the cumulative effect of genetic polymorphisms within the dopamine, norepinephrine, and serotonin neurotransmitter pathways with ADHD susceptibility. A case-control study was conducted among Chinese children, and 168 ADHD patients and 233 controls were recruited using a combination diagnosis according to the DSM-IV ADHD rating scale. Classification and regression tree (CART) analysis was conducted to explore the gene-gene interaction, and logistic regression modal was applied to estimate the polygenic risk of the potential multiple genetic variants. The results of CART analyses indicated that the children carrying the combination of ADRA2A rs553668GG/GA and SLC6A4 rs6354 GG/GT genotypes displayed a 6.15-fold increased risk of ADHD, compared to those with the combination of ADRA2A rs553668 AA and ANKK1 rs1800497 AA genotypes. The unfavorable alleles of ADRA2A rs553668 G, DRD2 rs1124491 G and SLC6A4 rs6354 G showed cumulative effects on ADHD, and the OR for ADHD may increase by 1.42 times when the number of unfavorable allele number increased by one. Those findings reveal the importance of the gene-gene interactions and polygenic effects of many common variants to ADHD susceptibility, even the effect of each variant is very small.

Host and gut microbial tryptophan metabolism and type 2 diabetes: an integrative analysis of host genetics, diet, gut microbiome and circulating metabolites in cohort studies

ObjectiveTryptophan can be catabolised to various metabolites through host kynurenine and microbial indole pathways. We aimed to examine relationships of host and microbial tryptophan metabolites with incident type 2 diabetes...

Ranking the risk of heart disease

By accounting for the additive effect of multiple genetic variants, researchers can develop a system that improves their ability to identify the most vulnerable. By accounting for the additive effect of multiple genetic variants, researchers can develop a system that improves their ability to identify the most vulnerable.

Prostate cancer risk variants of the HOXB genetic locus

The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case–control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E−9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E−11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E−8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.

Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test.

Cutaneous squamous cell carcinoma (cSCC) accounts for about 20% of all skin cancers, the most common type of malignancy in the United States. Genome-wide association studies (GWAS) have successfully identified multiple genetic variants associated with the risk of cSCC. Most of these studies were single-locus-based, testing genetic variants one-at-a-time. In this article, we performed gene-based association tests to evaluate the joint effect of multiple variants, especially rare variants, on the risk of cSCC by using a fast sequence kernel association test (fastSKAT). The study included 1,710 cSCC cases and 24,304 cancer-free controls from the Nurses’ Health Study, the Nurses’ Health Study II and the Health Professionals Follow-up Study. We used UCSC Genome Browser to define gene units as candidate loci, and further evaluated the association between all variants within each gene unit and disease outcome. Four genes HP1BP3, DAG1, SEPT7P2, and SLFN12 were identified using Bonferroni adjusted significance level. Our study is complementary to the existing GWASs, and our findings may provide additional insights into the etiology of cSCC. Further studies are needed to validate these findings.

Predicting anthropometric and metabolic traits with a genetic risk score for obesity in a sample of Pakistanis

Obesity is an outcome of multiple factors including environmental and genetic influences. Common obesity is a polygenic trait indicating that multiple genetic variants act synergistically to influence its expression. We constructed a genetic risk score (GRS) based on five genetic variants (MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752) and examined its association with obesity-related traits in a sample of Pakistanis. The study involved 306 overweight/obese (OW/OB) and 300 normal-weight (NW) individuals. The age range of the study participants was 12–63 years. All anthropometric and metabolic parameters were measured for each participant via standard procedures and biochemical assays, respectively. The genetic variants were genotyped by allelic discrimination assays. The age- and gender-adjusted associations between the GRS and obesity-related anthropometric and metabolic measures were determined using linear regression analyses. The results showed that OW/OB individuals had significantly higher mean ranks of GRS than NW individuals. Moreover, a significant association of the GRS with obesity-related anthropometric traits was seen. However, the GRS did not appear to affect any obesity-related metabolic parameter. In conclusion, our findings indicate the combined effect of multiple genetic variants on the obesity-related anthropometric phenotypes in Pakistanis.

Short Stature Syndromes: Case Series from India.

Syndromes causing short stature include Noonan syndrome (NS), Williams syndrome, and Silver-Russell syndrome (SRS). SRS is a primordial dwarfism with genetic heterogeneity. The SRS children present with prenatal growth retardation, neonatal hypoglycemia, feeding difficulties, physical asymmetry, with scoliosis and cardiac defect in some cases. The incidence is up to 1 in 100,000. Uniparental disomy, methylation abnormalities, and variants in some genes have been found underlying such phenotype. Growth hormone therapy has been used to improve the height gain in these patients. NS has genetic heterogeneity and most patients present with short stature with or without cardiac defect. Multiple genetic variants, mostly autosomal dominant, contribute to the phenotype. With the availability of next-generation sequencing, more and more genetic disorders causing short stature are being identified in different ethnic populations like Kabuki syndrome and Nance-Horan syndrome. Here, we present some cases of SRS and other additional syndromes with dysmorphism seen in past 5 years.

Multiple genetic variations of chronic rhinosinusitis with nasal polyps are associated with respiratory parameters in men with obstructive sleep apnea

PurposePatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have a higher risk of obstructive sleep apnea (OSA). However, the relationship between CRSwNP and OSA remains unclear. The aim of this research study was to evaluate the association of multiple single nucleotide polymorphism (SNP) variations in CRSwNP with sleep- and breath-related parameters in men with OSA.MethodsWe included eight CRSwNP SNPs in 2320 participants after strict screening. For each participant, the genetic risk score (GRS) was calculated based on the cumulative effect of multiple genetic variants of CRSwNP. A bivariate correlation analysis was used to assess the relationship between CRSwNP genetic polymorphisms and polysomnography parameters in men with OSA. Logistic regression analyses were used to assess the relationship between the risk of OSA and CRSwNP genetic polymorphisms.ResultsIn moderate OSA, rs28383314 was related to the oxygen desaturation index, and rs4807532 was positively associated with the microarousal index (r = 0.09, P = 0.03 and r = 0.11, P = 0.01, respectively). The CRSwNP GRS was positively correlated with the oxygen desaturation index and cumulative time percentage with SpO2 < 90% in moderate OSA (r = 0.13, P < 0.001 and r = 0.1, P = 0.01, respectively). There was no association between the CRSwNP GRS and the risk of OSA (OR = 1.007; 95% CI, 0.973–1.042; P = 0.702).ConclusionIn men with moderate OSA, single CRSwNP genetic variations correlated with sleep-related parameters, and the cumulative effects of CRSwNP genetic variations were associated with the hypoxic index. CRSwNP may be a predisposing condition for sleep disorders in men with moderate OSA.

Mendelian Randomization With Refined Instrumental Variables From Genetic Score Improves Accuracy and Reduces Bias.

Mendelian randomization (MR) can estimate the causal effect for a risk factor on a complex disease using genetic variants as instrument variables (IVs). A variety of generalized MR methods have been proposed to integrate results arising from multiple IVs in order to increase power. One of the methods constructs the genetic score (GS) by a linear combination of the multiple IVs using the multiple regression model, which was applied in medical researches broadly. However, GS-based MR requires individual-level data, which greatly limit its application in clinical research. We propose an alternative method called Mendelian Randomization with Refined Instrumental Variable from Genetic Score (MR-RIVER) to construct a genetic IV by integrating multiple genetic variants based on summarized results, rather than individual data. Compared with inverse-variance weighted (IVW) and generalized summary-data-based Mendelian randomization (GSMR), MR-RIVER maintained the type I error, while possessing more statistical power than the competing methods. MR-RIVER also presented smaller biases and mean squared errors, compared to the IVW and GSMR. We further applied the proposed method to estimate the effects of blood metabolites on educational attainment, by integrating results from several publicly available resources. MR-RIVER provided robust results under different LD prune criteria and identified three metabolites associated with years of schooling and additional 15 metabolites with indirect mediation effects through butyrylcarnitine. MR-RIVER, which extends score-based MR to summarized results in lieu of individual data and incorporates multiple correlated IVs, provided a more accurate and powerful means for the discovery of novel risk factors.

Clinical Impact of the Adaptation of Initial Tacrolimus Dosing to the CYP3A5 Genotype After Kidney Transplantation: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

The aim of this systematic review and meta-analysis was to compare the clinical outcomes between genotype-guided and conventional tacrolimus doses in kidney transplantation patients. We performed a comprehensive literature search of the PubMed, EMBASE, and Cochrane databases from the date of inception to 26 February 2020. References of the retrieved articles were also reviewed and any further relevant studies were included. The search terms included 'tacrolimus', 'cytochrome P-450 CYP3A', 'polymorphism, genetic', 'genomics', 'genome', 'genotype', 'genes', 'alleles', and 'pharmacogenetics'. Our study showed that the genotype-guided group included an increased proportion of patients with tacrolimus concentrations in the therapeutic range at steady state (risk ratio [RR] 1.40, 95% confidence interval [CI] 1.14-1.72, p=0.001; high quality), with a trend for achieving therapeutic concentrations earlier compared with those in the conventional group. However, there was no statistical difference in the incidence of delayed graft function (RR 1.98, 95% CI 0.92-1.76, p=0.12; moderate quality), incidence of acute rejection (RR 1.00, 95% CI 0.64-1.55, p=1.00; moderate quality), incidence of graft survival censored for death (RR 1.02, 95% CI 0.98-1.06, p=0.37; moderate quality), and incidence of adverse effects (AEs). Although the genotype-guided group had a higher proportion of patients within the targeted concentration and less median time to achieve the therapeutic range, the clinical endpoints, including delayed graft function, acute rejection, graft survival censored for death, and AEs were similar in both groups. All in all, evidence suggested there was no utility in pharmacogenetics for tacrolimus based on the cytochrome P450 (CYP)3A5 genotype. Studies with Chinese and African American populations are needed due to the frequency of genetic polymorphisms of CYP3A5. Furthermore, a dosing algorithm that includes demographic and clinical factors plus multiple genetic variants should be added for consideration, and may optimize early tacrolimus exposure.

PDE11A gene polymorphism in testicular cancer: sperm parameters and hormonal profile

PurposeTesticular germ cell tumours (TGCTs) is the most common malignancy among young adult males. The etiology is multifactorial and both environmental and genetic factors play an important role in the origin and development of TGCT. Genetic susceptibility may result from the interaction of multiple common and low-penetrance genetic variants and one of the main candidate genes is PDE11A. Many PDE11A polymorphisms were found responsible for a reduced PDE activity in TGCT patients, who often also display impaired hormone and sperm profile. The aim of this study was to investigate testicular function and PDE11A sequence in testicular cancer cases.MethodsSemen analysis was performed in 116 patients with unilateral and bilateral sporadic TGCTs and in 120 cancer-free controls. We also investigated hormone profile and PDE11A polymorphisms using peripheral blood samples.ResultsOur data revealed that TGCT patients showed lower testosterone levels, higher gonadotropins levels and worse semen quality than controls, although the mean and the medians of sperm parameters are within the reference limits. PDE11A sequencing detected ten polymorphisms not yet associated with TGCTs before. Among these, G223A in homozygosity and A288G in heterozygosity were significantly associated with a lower risk of testicular tumour and they displayed a positive correlation with total sperm number.ConclusionsOur findings highlight the key role of PDE11A in testis and suggest the presence of an underlying complex and fine molecular mechanism which controls testis-specific gene expression and susceptibility to testicular cancer.

Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.

Associating Multivariate Traits with Genetic Variants Using Collapsing and Kernel Methods with Pedigree- or Population-Based Studies.

In genetic association analysis, several relevant phenotypes or multivariate traits with different types of components are usually collected to study complex or multifactorial diseases. Over the past few years, jointly testing for association between multivariate traits and multiple genetic variants has become more popular because it can increase statistical power to identify causal genes in pedigree- or population-based studies. However, most of the existing methods mainly focus on testing genetic variants associated with multiple continuous phenotypes. In this investigation, we develop a framework for identifying the pleiotropic effects of genetic variants on multivariate traits by using collapsing and kernel methods with pedigree- or population-structured data. The proposed framework is applicable to the burden test, the kernel test, and the omnibus test for autosomes and the X chromosome. The proposed multivariate trait association methods can accommodate continuous phenotypes or binary phenotypes and further can adjust for covariates. Simulation studies show that the performance of our methods is satisfactory with respect to the empirical type I error rates and power rates in comparison with the existing methods.

Familial Hypercholesterolemia: A Narrative Review on Diagnosis and Management Strategies for Children and Adolescents.

Familial hypercholesterolemia (FH) is a relatively common inherited disorder caused by deleterious mutation(s) in the low-density lipoprotein (LDL) receptor or its associated genes. Given its nature as a heritable disease, any useful screening scheme, including universal, and cascade screening, allows for the early identification of patients with FH. Another important aspect to note is that early diagnosis associated with appropriate treatment can promote better prognosis. However, most clinical diagnostic criteria for adults have adopted clinical elements, such as physical xanthomas and family history, both of which are usually obscure and/or difficult to obtain in children and adolescents. Moreover, LDL cholesterol levels fluctuating considerably during adolescence, hindering the timely diagnosis of FH. In addition, recent advancements in human genetics have revealed several types of FH, including conventional monogenic FH, polygenic FH caused by common single nucleotide variations (SNV) accumulation associated with elevated LDL cholesterol, and oligogenic FH with multiple deleterious genetic variations leading to substantially elevated LDL cholesterol. The aforementioned findings collectively suggest the need for amassing information related to genetics and imaging, in addition to classical clinical elements, for the accurate diagnosis of FH in this era of personalized medicine. The current narrative review summarizes the current status of the clinical and genetic diagnosis of FH in children and adolescents, as well as provide useful management strategies for FH in children and adolescents based on currently available clinical evidence.

Heterogeneity of a dwarf phenotype in Dutch traditional chicken breeds revealed by genomic analyses.

The growth of animals is a complex trait, in chicken resulting in a diverse variety of forms, caused by a heterogeneous genetic basis. Bantam chicken, known as an exquisite form of dwarfism, has been used for crossbreeding to create corresponding dwarf counterparts for native fowls in the Dutch populations. Here, we demonstrate the heterogeneity of the bantam trait in Dutch chickens and reveal the underlying genetic causes, using whole‐genome sequence data from matching pairs of bantam and normal‐sized breeds. During the bantam‐oriented crossbreeding, various bantam origins were used to introduce the bantam phenotype, and three major bantam sources were identified and clustered. The genome‐wide association studies revealed multiple genetic variants and genes associated with bantam phenotype, including HMGA2 and PRDM16, genes involved in body growth and stature. The comparison of associated variants among studies illustrated differences related to divergent bantam origins, suggesting a clear heterogeneity among bantam breeds. We show that in neo‐bantam breeds, the bantam‐related regions underwent a strong haplotype introgression from the bantam source, outcompeting haplotypes from the normal‐sized counterpart. The bantam heterogeneity is further confirmed by the presence of multiple haplotypes comprising associated alleles, which suggests the selection of the bantam phenotype is likely subject to a convergent direction across populations. Our study demonstrates that the diverse history of human‐mediated crossbreeding has contributed to the complexity and heterogeneity of the bantam phenotype.

Generalized multi-SNP mediation intersection-union test.

To elucidate the molecular mechanisms underlying genetic variants identified from genome-wide association studies (GWAS) for a variety of phenotypic traits encompassing binary, continuous, count, and survival outcomes, we propose a novel and flexible method to test for mediation that can simultaneously accommodate multiple genetic variants and different types of outcome variables. Specifically, we employ the intersection-union test approach combined with the likelihood ratio test to detect mediation effect of multiple genetic variants via some mediator (e.g., the expression of a neighboring gene) on outcome. We fit high-dimensional generalized linear mixed models under the mediation framework, separately under the null and alternative hypothesis. We leverage Laplace approximation to compute the marginal likelihood of outcome and use coordinate descent algorithm to estimate corresponding parameters. Our extensive simulations demonstrate the validity of our proposed methods and substantial, up to 97%, power gains over alternative methods. Applications to real data for the study of Chlamydia trachomatis infection further showcase advantages of our methods. We believe our proposed methods will be of value and general interest in this post-GWAS era to disentangle the potential causal mechanism from DNA to phenotype for new drug discovery and personalizedmedicine.

PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/β-Catenin Response to Suppress Apc Min-Triggered Intestinal Tumor Formation.

Genetic predisposition affects the penetrance of tumor-initiating mutations, such as APC mutations that stabilize β-catenin and cause intestinal tumors in mice and humans. However, the mechanisms involved in genetically predisposed penetrance are not well understood. Here, we analyzed tumor multiplicity and gene expression in tumor-prone Apc Min/+ mice on highly variant C57BL/6J (B6) and PWD/Ph (PWD) genetic backgrounds. (B6 × PWD) F1 APC Min offspring mice were largely free of intestinal adenoma, and several chromosome substitution (consomic) strains carrying single PWD chromosomes on the B6 genetic background displayed reduced adenoma numbers. Multiple dosage-dependent modifier loci on PWD chromosome 5 each contributed to tumor suppression. Activation of β-catenin-driven and stem cell-specific gene expression in the presence of Apc Min or following APC loss remained moderate in intestines carrying PWD chromosome 5, suggesting that PWD variants restrict adenoma initiation by controlling stem cell homeostasis. Gene expression of modifier candidates and DNA methylation on chromosome 5 were predominantly cis controlled and largely reflected parental patterns, providing a genetic basis for inheritance of tumor susceptibility. Human SNP variants of several modifier candidates were depleted in colorectal cancer genomes, suggesting that similar mechanisms may also affect the penetrance of cancer driver mutations in humans. Overall, our analysis highlights the strong impact that multiple genetic variants acting in networks can exert on tumor development. SIGNIFICANCE: These findings in mice show that, in addition to accidental mutations, cancer risk is determined by networks of individual gene variants.

New novel non-MHC genes were identified for cervical cancer with an integrative analysis approach of transcriptome-wide association study.

Although genome-wide association studies (GWAS) have successfully identified multiple genetic variants associated with cervical cancer, the functional role of those variants is not well understood. To bridge such gap, we integrated the largest cervical cancer GWAS (N = 9,347) with gene expression measured in six human tissues to perform a multi-tissue transcriptome-wide association study (TWAS). We identified a total of 20 associated genes in the European population, especially four novel non-MHC genes (i.e. WDR19, RP11-384K6.2, RP11-384K6.6 and ITSN1). Further, we attempted to validate our results in another independent cervical cancer GWAS from the East Asian population (N = 3,314) and re-discovered four genes including WDR19, HLA-DOB, MICB and OR2B8P. In our subsequent co-expression analysis, we discovered SLAMF7 and LTA were co-expressed in TCGA tumor samples and showed both WDR19 and ITSN1 were enriched in “plasma membrane”. Using the protein-protein interaction analysis we observed strong interactions between the proteins produced by genes that are associated with cervical cancer. Overall, our study identified multiple candidate genes, especially four non-MHC genes, which may be causally associated with the risk of cervical cancer. However, further investigations with larger sample size are warranted to validate our findings in diverse populations.