Individual Single Nucleotide Polymorphisms Research Articles

Genomic Prediction Using LD-Based Haplotypes Inferred From High-Density Chip and Imputed Sequence Variants in Chinese Simmental Beef Cattle.

A haplotype is defined as a combination of alleles at adjacent loci belonging to the same chromosome that can be transmitted as a unit. In this study, we used both the Illumina BovineHD chip (HD chip) and imputed whole-genome sequence (WGS) data to explore haploblocks and assess haplotype effects, and the haploblocks were defined based on the different LD thresholds. The accuracies of genomic prediction (GP) for dressing percentage (DP), meat percentage (MP), and rib eye roll weight (RERW) based on haplotype were investigated and compared for both data sets in Chinese Simmental beef cattle. The accuracies of GP using the entire imputed WGS data were lower than those using the HD chip data in all cases. For DP and MP, the accuracy of GP using haploblock approaches outperformed the individual single nucleotide polymorphism (SNP) approach (GBLUP_In_Block) at specific LD levels. Hotelling’s test confirmed that GP using LD-based haplotypes from WGS data can significantly increase the accuracies of GP for RERW, compared with the individual SNP approach (∼1.4 and 1.9% for GHBLUP and GHBLUP+GBLUP, respectively). We found that the accuracies using haploblock approach varied with different LD thresholds. The LD thresholds (r2 ≥ 0.5) were optimal for most scenarios. Our results suggested that LD-based haploblock approach can improve accuracy of genomic prediction for carcass traits using both HD chip and imputed WGS data under the optimal LD thresholds in Chinese Simmental beef cattle.

Associations Among Parental Caregiving Quality, Cannabinoid Receptor 1 Expression-Based Polygenic Scores, and Infant-Parent Attachment: Evidence for Differential Genetic Susceptibility?

Attachment is a biological evolutionary system contributing to infant survival. When primary caregivers/parents are sensitive and responsive to their infants’ needs, infants develop a sense of security. Secure infant attachment has been linked to healthy brain and organ-system development. Belsky and colleagues proposed the term differential susceptibility to describe context-dependent associations between genetic variations and behavioral outcomes as a function of parenting environments. Variations in the Cannabinoid Receptor Gene 1 (CNR1) are associated with memory, mood, and reward and connote differential susceptibility to more and less optimal parental caregiving quality in predicting children’s behavioral problems.AimTo determine if parental caregiving quality interacts with children’s expression-based polygenic risk score (ePRS) for the CNR1 gene networks in the prefrontal cortex, striatum, and hippocampus in predicting the probability of attachment security and disorganized attachment.DesignProspective correlational methods examined maternal-infant pairs (n = 142) from which infants provided DNA samples at 3 months. Parental caregiving quality was assessed via the Child Adult Relationship Experiment (CARE)-index at 6 months, and attachment security via the Strange Situation Procedure at a mean age of 22 months. The CNR1 ePRSs include genes co-expressed with the CNR1 genes in the prefrontal cortex, striatum, or hippocampus, and were calculated using the effect size of the association between the individual single nucleotide polymorphisms from those genes and region-specific gene expression (GTEx). Logistic regression was employed (alpha < 0.05, two-tailed) to examine the main and interaction effects between parental caregiving quality and ePRSs in predicting attachment patterns. Interpretation of results was aided by analyses that distinguished between differential susceptibility and diathesis-stress.ResultsSignificant interactions were observed between (1) maternal sensitivity and ePRS in the striatum in predicting attachment security, (2) maternal unresponsiveness with the ePRS in the hippocampus in predicting disorganization, and (3) maternal controlling with the ePRS in the hippocampus in predicting disorganization.ConclusionThese findings offer support for genetic differential susceptibility to the quality of maternal sensitivity in the context of the ePRS in the striatum. However, the significant interactions between hippocampal ePRS and maternal unresponsiveness and controlling in predicting the probability of disorganization were more suggestive of the diathesis-stress model.

Common Genetic Polymorphisms Contribute to the Association between Non-Melanoma Skin Cancer and Chronic Lymphocytic Leukemia

Introduction: Genome-wide association studies (GWAS) have identified thousands of genetic variants associated with numerous traits and diseases. The analysis of shared genetic associations between diseases can help explain previously found epidemiological associations and provide better insight into disease etiology. Epidemiological studies have demonstrated a consistent positive association between chronic lymphocytic leukemia (CLL) and non-melanoma skin cancers (NMSC); however, the reasons for this association are not well understood. We explored the hypothesis that shared genetic risk factors between CLL and NMSC could contribute to the epidemiological association observed between these diseases.Methods: We identified established loci associated with CLL or NMSC with p<5x10-8 based on published results. Single nucleotide polymorphisms (SNPs) were considered independent if they were ≥500 kb apart and had r2<0.05. We examined the association between NMSC loci and CLL risk in a pooled GWAS of CLL including 3,100 cases and 7,667 controls of European ancestry. In parallel, we investigated the association between CLL loci and NMSC risk in a study of 4,242 basal cell carcinoma (BCC) cases and 12,802 controls and also 825 squamous cell carcinoma (SCC) cases and 11,518 controls. Weighted genetic risk scores (wGRS) were constructed separately for each disease. For each SNP, the odds ratios (OR) for the association with NMSC or CLL was extracted from existing literature. In the wGRS, the number of risk alleles was multiplied by the log-OR of that SNP as reported in the literature. We estimated the OR and 95% confidence interval (95% CI) for the associations with individual SNPs and with the wGRS for both CLL and NMSC using logistic regression, adjusting for age, sex, and principal components to account for population substructure.Results: Six of the established genetic loci for CLL and NMSC overlapped such that at least SNPs associated with CLL and NMSC were within a 1 Mb: 2q33.1, 3q28, 5p15, 6p21, 6p25 and 9q21.Of the reported NMSC loci, 4 index SNPs were nominally associated with CLL risk after adjustment for multiple testing (PFDR-adjusted≤0.05): rs12203592 and rs12210050 at 6p25 (IRF4/EXOC2), rs78378222 at 17p13.1 (TP53), and rs191177147 at 3q28 (LPP). The most significant associations were at 6p25.3 region in the IRF4/EXOC2 locus: rs12203592 (OR: 1.41, 95% CI: 1.29-1.54, P=7.34 x 10-14) and rs12210050 (OR=1.23, 95% CI: 1.12-1.35, P=1.97 x 10-5). Using the wGRS from SCC SNPs, we found a pattern of increasing risk of CLL with increasing quartile, reaching statistical significance for quartile 4 vs. quartile 1 (OR=1.26, 95% CI: 1.14-1.39, P=0.001). After excluding the IRF4 polymorphism rs12203592, the association between the wGRS and CLL was no longer significant (OR=1.02, 95% CI: 0.90-1.45, P=0.81).Of the reported CLL SNPs, five were associated with NMSC risk after adjustment for multiple testing (PFDR-adjusted≤0.05): rs9815073 at 3q28 (LPP), rs3769825 at 2q33 (CASP10/CASP8), rs17246404 at 7q31 (POT1), rs4368253 at 18q21 (PMAIP1) and rs872071 at 6p25 (IRF4/EXOC2). The wGRS based on the CLL SNPs was associated with BCC risk (P=0.004) but not with SCC risk (P=0.12), possibly due to a lack of statistical power. Of note, after exclusion of the IRF4 polymorphism, the association between the wGRS and BCC remained statistically significant (P=0.02).Conclusion: We report here a novel and statistically significant association between the genetic burden for risk of NMSC and of CLL. Finally, we uncovered that polymorphisms in the Interferon Regulatory Factor 4 (IRF4) gene appear to contribute to the association between CLL and NMSC. IRF4, also known as multiple myeloma oncogene-1 (MUM1), is a transcriptional regulator expressed in lymphocytes and in melanocytes. Further studies are needed to understand the common biological mechanisms that lead to this association. Overall, these findings highlight the pleiotropic effect of genes in the pathogeneses of these cancers and suggest that they have a partially shared genetic etiology. DisclosuresSmedby:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Shanafelt:Genentech, Celgene, Pharamacyclics, Jansen, GlaxoSmithKline, AbbVie, Hospira, and Cephalon: Research Funding. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering.

Joint Effect of Multiple Prothrombotic Genotypes and Obesity on the Risk of Incident Venous Thromboembolism.

The impact of the combination of obesity and multiple prothrombotic genotypes on venous thromboembolism (VTE) risk remains unclear. To investigate the joint effect of obesity and a genetic risk score (GRS) composed of established prothrombotic single nucleotide polymorphisms (SNPs) on VTE risk using a population-based case-cohort. Cases with incident VTE (n = 1,470) and a subcohort (n = 12,826) were derived from the Tromsø Study (1994-2012) and the Trøndelag Health Study (HUNT) (1995-2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865), and F11 (rs2036914) SNPs. Age- and sex-adjusted hazard ratios (HRs) were estimated according to body mass index (BMI) categories and number of risk alleles for individual SNPs and the GRS (0-1, 2, 3, ≥4 alleles). The combination of obesity (BMI ≥ 30kg/m2) and risk alleles, either as individual SNPs or as a GRS, had an additive effect on VTE risk (i.e., no biological interaction). Obese subjects who were carriers of ≥4 risk alleles had a 2.85-fold (95% confidence interval [CI]: 2.05-3.96) increased risk of overall VTE compared with those with BMI <25 kg/m2 and 0 to 1 risk allele. However, in subgroups, the combination of obesity and ≥4 risk alleles was more pronounced for deep vein thrombosis (DVT) (HR: 3.20; 95% CI: 2.09-4.90) and unprovoked VTE (HR: 3.82; 95% CI: 2.25-6.47), suggesting a supra-additive effect. Our findings indicate that the combination of obesity and GRS has an additive effect on the risk of overall VTE. However, it may have a supra-additive effect on the risk of DVT and unprovoked VTE.

Multitrait transcriptome-wide association study (TWAS) tests.

Multitrait tests can improve power to detect associations between individual single-nucleotide polymorphisms (SNPs) and several related traits. Here, we develop methods for multi-SNP transcriptome-wide association (TWAS) tests to test the association between predicted gene expression levels and multiple phenotypes. We show that the correlation in TWAS test statistics for multiple phenotypes has the same form as multitrait statistics for the single-SNP setting. Thus, established methods for combining single-SNP test statistics across multiple traits can be extended directly to the TWAS setting. We performed an extensive evaluation across eight multitrait methods in simulations that varied gene-phenotype effect sizes in addition to the underlying covariance structure among the phenotypes. We found that all multitrait TWAS tests have well-calibrated Type I error (except ASSET, which can have a slightly elevated or depressed Type I error rate). Our results show that multitrait TWAS can improve statistical power compared with multiple single-trait TWAS followed by Bonferroni correction. To illustrate our approach to real data, we conducted a multitrait TWAS of four circulating lipid traits from the Global Lipids Genetics Consortium. We found that our multitrait Wald TWAS approach identified 506 genes associated with lipid levelscompared with 87 identified through Bonferroni-corrected single-trait TWAS. Overall, we find that our proposed multitrait TWAS framework outperforms single-trait approaches to identify new genetic associations, especially for functionally correlated phenotypes and phenotypes with overlapping genome-wide association studies samples, leading to insights into the genetic architecture of multiple phenotypes.

Impact of FGFR4 Gene Polymorphism on the Progression of Colorectal Cancer.

Colorectal cancer (CRC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Fibroblast growth factor receptor 4 (FGFR4) is a receptor tyrosine kinase that has been shown to play a key role in cancer development and prognosis via the activation of its downstream oncogenic signaling pathways. The present study aimed to explore the impact of FGFR4 gene polymorphisms on the risk and progression of CRC. Three FGFR4 single-nucleotide polymorphisms (SNPs), including rs1966265, rs351855, and rs7708357, were evaluated in 413 CRC cases and 413 gender- and age-matched cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of CRC between the case and control group. However, while assessing the clinicopathological parameters, patients of rectal cancer possessing at least one minor allele of rs1966265 (AG and GG; AOR, 0.236; p = 0.046) or rs351855 (GA and AA; AOR, 0.191; p = 0.022) were found to develop less metastasis as compared to those who are homozygous for the major allele. Further analyses using the datasets from the Genotype-Tissue Expression (GTEx) Portal and The Cancer Genome Atlas (TCGA) revealed that rs351855 regulated FGFR4 expression in many human tissues, and increased FGFR4 levels were associated with the occurrence, advanced stage, and distal metastasis of colon adenocarcinoma. These data suggest that the amino acid change in combination with altered expression levels of FGFR4 due to genetic polymorphisms may affect CRC progression.

Association of LINC00673 Genetic Variants with Progression of Oral Cancer.

Oral squamous cell carcinoma (OSCC) is a multifactorial malignancy, and its high incidence and mortality rate remain a global public health burden. Polymorphisms in the long intergenic noncoding RNA 673 (LINC00673) have been currently connected to the predisposition to various cancer types. The present study attempted to explore the impact of LINC00673 gene polymorphisms on the risk and progression of OSCC. Three LINC00673 single-nucleotide polymorphisms (SNPs), including rs11655237, rs9914618, and rs6501551, were evaluated in 1231 OSCCC cases and 1194 cancer-free controls. We did not observe any significant association of three individual SNPs with the risk of OSCC between the case and control group. However, while assessing the clinicopathological parameters, patients carrying at least one minor allele of rs9914618 (GA and AA; OR, 1.286; 95% CI, 1.008–1.642; p = 0.043) were found to develop lymph node metastasis more often compared to those who are homozygous for the major allele. Further stratification analyses revealed that this genetic correlation with increased risk of lymphatic spread was further fortified in habitual betel quid chewers (OR, 1.534; 95% CI, 1.160–2.028; p = 0.003) or smokers (OR, 1.320; 95% CI, 1.013–1.721; p = 0.040). Moreover, through analyzing the dataset from The Cancer Genome Atlas (TCGA), we found that elevated LINC00673 levels were associated with the development of large tumors in patients with head and neck squamous cell carcinoma and the risk of lymphatic spread in smokers. These data demonstrate a joint effect of LINC00673 rs9914618 with betel nut chewing or smoking on the progression of oral cancer.

Pharmacogenetic association of diabetes-associated genetic risk score with rapid progression of coronary artery calcification following treatment with HMG-CoA-reductase inhibitors \u2014results of the Heinz Nixdorf Recall Study

HMG-CoA-Reductase inhibitors (HMGRIs) are currently the most widely used group of drugs in patients with coronary artery disease (CAD) and are given preemptively to patients with high levels of cholesterol, including those with diabetes mellitus (DM). However, intake of HMGRIs also increases the progression of coronary artery calcification (CAC) and the risk of developing DM. This study aimed to investigate whether HMGRI intake interacts with the diabetes-associated genetic risk score (GRS) to affect CAC progression using data from the population-based Heinz Nixdorf Recall (HNR) study. CAC was measured in 3157 participants using electron-beam computed tomography twice, at baseline (CACb) and 5 years later (CAC5y). CAC progression was classified as slow, expected, or rapid based on predicted values. Weighted DM GRS was constructed using 100 diabetes mellitus–associated single nucleotide polymorphisms (SNPs). We used log-linear regression to evaluate the interaction of HMGRI intake with diabetes-associated GRS and individual SNPs on CAC progression (rapid vs. expected/slow), adjusting for age, sex, and log(CACb + 1). The prevalence of rapid CAC progression in the HNR study was 19.6%. We did not observe any association of the weighted diabetes mellitus GRS with the rapid progression of CAC (relative risk (RR) [95% confidence interval (95% CI)]: 1.01 [0.94; 1.10]). Furthermore, no indication of an interaction between GRS and HMGRI intake was observed (1.08 [0.83; 1.41]). Our analyses showed no indication that the impact of HMGRIs on CAC progression is significantly more severe in patients with a high genetic risk of developing DM than in those with a low GRS.

Single nucleotide polymorphisms of the interleukin-1 superfamily members: аssociation with viral hepatitis B and C

The review provides information on single nucleotide polymorphisms (SNPs) in genes encoding some interleukins belonging to the interleukin-1 (IL-1) superfamily and on their association with different infectious and non-infectious human diseases. It also briefs on the history of SNP discovery and the progress in the related scientific studies till the present time. It gives an insight into some mechanisms of interaction between infectious agents and the human immune system, involving SNPs in some cytokines of the IL-1 superfamily. The review provides data on relationships of SNPs in genes encoding other factors of the immune system, which are associated with the specific characteristics of natural history of chronic hepatitis B and C. It explores the significance of assessment of the SNP-proportion in proinflammatory cytokines and their antagonists of the IL-1 superfamily among the healthy population as well as the ratio of individual SNPs in specific groups of patients as a monitoring parameter for epidemiological surveillance of infectious diseases.

Molecular Parallelism Underlies Convergent Highland Adaptation of Maize Landraces.

Convergent phenotypic evolution provides some of the strongest evidence for adaptation. However, the extent to which recurrent phenotypic adaptation has arisen via parallelism at the molecular level remains unresolved, as does the evolutionary origin of alleles underlying such adaptation. Here, we investigate genetic mechanisms of convergent highland adaptation in maize landrace populations and evaluate the genetic sources of recurrently selected alleles. Population branch excess statistics reveal substantial evidence of parallel adaptation at the level of individual single-nucleotide polymorphism (SNPs), genes, and pathways in four independent highland maize populations. The majority of convergently selected SNPs originated via migration from a single population, most likely in the Mesoamerican highlands, while standing variation introduced by ancient gene flow was also a contributor. Polygenic adaptation analyses of quantitative traits reveal that alleles affecting flowering time are significantly associated with elevation, indicating the flowering time pathway was targeted by highland adaptation. In addition, repeatedly selected genes were significantly enriched in the flowering time pathway, indicating their significance in adapting to highland conditions. Overall, our study system represents a promising model to study convergent evolution in plants with potential applications to crop adaptation across environmental gradients.

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia). CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE. Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.

Telomere Length and Male Fertility.

Over the past decade, telomeres have attracted increasing attention due to the role they play in human fertility. However, conflicting results have been reported on the possible association between sperm telomere length (STL) and leukocyte telomere length (LTL) and the quality of the sperm parameters. The aim of this study was to run a comprehensive study to investigate the role of STL and LTL in male spermatogenesis and infertility. Moreover, the association between the sperm parameters and 11 candidate single nucleotide polymorphisms (SNPs), identified in the literature for their association with telomere length (TL), was investigated. We observed no associations between sperm parameters and STL nor LTL. For the individual SNPs, we observed five statistically significant associations with sperm parameters: considering a p < 0.05. Namely, ACYP2˗rs11125529 and decreased sperm motility (p = 0.03); PXK˗rs6772228 with a lower sperm count (p = 0.02); NAF1˗rs7675998 with increased probability of having abnormal acrosomes (p = 0.03) and abnormal flagellum (p = 0.04); ZNF208˗rs8105767 and reduction of sperms with normal heads (p = 0.009). This study suggests a moderate involvement of telomere length in male fertility; however, in our analyses four SNPs were weakly associated with sperm variables, suggesting the SNPs to be pleiotropic and involved in other regulatory mechanisms independent of telomere homeostasis, but involved in the spermatogenic process.

Association of Nucleotide Variants of GRHL3, IRF6, NAT2, SDC2, BCL3, and PVRL1 Genes with Nonsyndromic Cleft Lip With/Without Cleft Palate in Multigenerational Families: A Retrospective Study.

Background:Several genes are associated with the etiology of cleft lip and palate (CLP) in different populations. Many nucleotide variants on genes such as GRHL3, IRF6, NAT2, SDC2, BCL3, and PVRL1 were reported in different populations, but not studied in multigenerational cases in the Indian population.Aim and Objective:The aim of this study is to evaluate whether nucleotide variants rs41268753, rs861020, rs1041983, rs1042381, rs2965169, and rs10790332 are involved in the etiology of nonsyndromic CLP (NSCLP) in multigenerational Indian families.Study Design:Retrospective genetic study.Materials and Methods:Based on inclusion and exclusion criteria, 20 multigenerational families with nonsyndromic cleft lip with or without cleft palate (NSCL/P) were selected. Blood samples from both affected and unaffected participants were collected as a source of genomic DNA. Six nucleotide variants on these genes were genotyped to test for the association with NSCL/P. Genotyping was performed with the MassArray method. Genotype distribution was used to calculate the Hardy–Weinberg equilibrium using PLINK, a whole-genome association analysis toolset. The allelic association was compared among cases and controls using Chi-square test as implemented in PLINK. P ≤ 0.05 indicates statistical differences between groups.Results:No significant associations were found between individual single-nucleotide polymorphisms and NSCL/P. The odds ratio was 1.531, 1.198, 0.8082, 1.418, 1, and 0.5929 for polymorphisms rs41268753, rs861020, rs1041983, rs1042381, rs2965169, and rs10790332, respectively.Conclusion:Our findings suggest that among the multigenerational families in our population, the high-risk nucleotide variants GRHL3 rs41268753, IRF6 rs861020, NAT2 rs1041983, SDC2 rs1042381, BCL3 rs2965169, and PVRL1 rs10790332 are not associated with increased risk of NSCL/P.

Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study.

Background:Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated.Objectives:We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.Methods:We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).Results:We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6–10% lower in carriers compared with noncarriers in HEALS [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )].Discussion:Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5–0.7%) carry these variants, they are associated with a 6–10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152

Evaluation of a Custom SNP Panel for Identifying and Rectifying of Misjudged Paternity in Deficiency Cases.

Parentage testing is routinely performed by genotyping short tandem repeat (STR) through capillary electrophoresis in the present. However, ambiguous or even misjudged paternity based on STRs happens from time to time in cases where only one putative parent is available. We analyzed STR data of 7,818,969 unrelated pairs and 75 close-relative pairs and found that although the probability of a random false match between non-relatives was 4.22 × 10–6, the incidence of false or ambiguous paternity results between children and first-degree relatives of their true parent was as high as 18.67%. These results highlight the risk of false inclusion of a relative or even non-relatives in parentage testing with STRs. We then validated all ambiguous STR results by targeted sequencing with a custom panel containing 4,830 individual identification single nucleotide polymorphisms (IISNP), found that the ratio of mismatch loci to total SNPs was 1.78–6.95% in close relatives compared with 10.93–13.49% in unrelated pairs. Last, we reported three real cases with undetermined paternity by STRs and rectified them by dissecting with our IISNP panel. These results suggested that high-density IISNP panel can be used to identify and rectify misjudged cases effectively.

Association of Genetic Polymorphisms in MicroRNAs With Type 2 Diabetes Mellitus in a Chinese Population.

IntroductionMicroRNAs (miRNA) involved in the insulin signaling pathways deeply affect the pathogenesis of T2DM. The aim of this study was to assess the association between single nucleotide polymorphisms (SNP) of the related miRNAs (let-7f rs10877887, let-7a-1 rs13293512, miR-133a-1 rs8089787, miR-133a-2 rs13040413, and miR-27a rs895819) and susceptibility to type 2 diabetes mellitus (T2DM), and its possible mechanisms.MethodsFive SNPs in miRNAs (let-7f rs10877887, let-7a-1 rs13293512, miR-133a-1 rs8089787, miR-133a-2 rs13040413, and miR-27a rs895819) involved in the insulin signaling pathways were selected and genotyped in a case-control study that enrolled 371 T2DM patients and 381 non-diabetic controls. The individual SNP association analyses, interaction analyses of SNP-SNP, SNP-environmental factors were performed. The effect the risk-associated polymorphism on regulating its mature miRNA expression was also evaluated.ResultsIn overall analyses, miR-133a-2 rs13040413 and let-7a-1 rs13293512 were related to the susceptibility to T2DM. In stratified analyses, miR-133a-2 rs13040413, let-7a-1 rs13293512 and miR-27a rs895819 showed associations with T2DM in the age ≥ 60 years subgroup. Moreover, let-7a-1 rs13293512 and miR-27a rs895819 showed associations with T2DM in male subgroup. In SNP-environmental factors interaction analyses, there were interaction effects of miR-133a-2 rs13040413 with dyslipidemia, let-7a-1 rs13293512 with smoking, and let-7a-1 rs13293512 with dyslipidemia on T2DM. In SNP-SNP interaction analyses, there were also interaction effects of miR-133a-1 rs8089787 with let-7a-1 rs13293512, and miR-133a-1 rs8089787 with let-7f rs10877887 on T2DM. Furthermore, for miR-133a-2 rs13040413, the variant T allele showed a trend toward decreased miR-133a expression in comparison with the wild C allele. For let-7a-1 rs13293512, the variant C allele expressed a lower let-7a compared to the wild T allele.ConclusionMiRNAs polymorphisms involved in the insulin signaling pathways and the interaction effects of SNP-SNP, SNP-environmental factors were related to T2DM susceptibility in a Chinese population.

Genetic polymorphisms in TCF7L2 and PPARG genes and susceptibility to Type 2 diabetes mellitus

Transcription factor 7-like 2 (TCF7L2) plays an important role in insulin resistance and peroxisome proliferator-activated receptor γ (PPARG) is directly targeted by antidiabetic drug. This study was designed to investigate the association of genetic variants in TCF7L2 and PPARG and T2DM susceptibility. Blood samples were collected from 472 subjects (221 controls and 251 T2DM cases) after ethical approval. All subjects were genotyped for two single nucleotide polymorphisms (SNPs) in each gene TCF7L2 (+9017G>T and -41435C>T) and PPARG (-44458C>G, -17676A>G) using polymerase chain reaction-restriction fragment length polymorphism (PCRRFLP) and amplification-refractory mutation system (ARMS-PCR). The TCF7L241435C>T polymorphism showed significantly higher frequency of 'TT' genotype in controls (12.2%) (P = 0.023). Haplotype 'GC*' of TCF7L2 (+9017G>T,-41435C>T) showed significant association with T2DM (P = 0.043). We conclude that individuals with 'GTG*' allelic combination were at significantly higher risk for T2DM (OR = 5.1, P=0.0002 respectively) whereas GCG* and GTA* allelic combinations showed significant protection against T2DM.The individual SNPs in TCF7L2 and PPARG genes were non-informative in genotyping analysis but showed significant risk for T2DM when analyzed together.

Relationships between accelerometer-measured and multiple sclerosis: a 2-sample Mendelian randomization study.

Observational studies suggest that physical activity (PA) can independently modify the risk of developing multiple sclerosis (MS). To investigate the causal effect of PA on MS by Mendelian randomization (MR) approaches. Through a genome-wide association study including 91,105 participants from UK Biobank, we obtained 5 single-nucleotide polymorphisms (SNPs) associated with accelerometer-measured PA (P < 5 × 10-8). Summary-level data for MS were obtained from a meta-analysis, incorporating 14,802 subjects with MS and 26,703 healthy controls of European ancestry. MR analyses were performed using the inverse-variance-weighted method, weighted median estimator, and MR-PRESSO method. Additional analyses were further performed using MR-Egger intercept and Cochran's Q statistic to verify the robustness of our findings. We failed to detect a causal effect of PA on MS (OR, 0.60; 95% confidence interval [CI], 0.30-1.20; P = 0.15) per in the random-effects IVW analysis. Additional MR methods yielded consistent results. MR-Egger regression suggested no evidence of horizontal pleiotropy (Intercept = 0.14, P = 0.21) and there seemed no substantial heterogeneity (I2 = 29.8%, P = 0.22) among individual SNPs. Our findings suggest that enhancing PA might not modify the risk of developing MS independent of established risk factors.

Investigation of gene-gene interactions of clock genes for chronotype in a healthy Korean population.

Chronotype is an important moderator of psychiatric illnesses, which seems to be controlled in some part by genetic factors. Clock genes are the most relevant genes for chronotype. In addition to the roles of individual genes, gene-gene interactions of clock genes substantially contribute to chronotype. We investigated genetic associations and gene-gene interactions of the clock genes BHLHB2, CLOCK, CSNK1E, NR1D1, PER1, PER2, PER3, and TIMELESS for chronotype in 1,293 healthy Korean individuals. Regression analysis was conducted to find associations between single nucleotide polymorphism (SNP) and chronotype. For gene-gene interaction analyses, the quantitative multifactor dimensionality reduction (QMDR) method, a nonparametric model-free method for quantitative phenotypes, were performed. No individual SNP or haplotype showed a significant association with chronotype by both regression analysis and single-locus model of QMDR. QMDR analysis identified NR1D1 rs2314339 and TIMELESS rs4630333 as the best SNP pairs among two-locus interaction models associated with chronotype (cross-validation consistency [CVC] = 8/10, p = 0.041). For the three-locus interaction model, the SNP combination of NR1D1 rs2314339, TIMELESS rs4630333, and PER3 rs228669 showed the best results (CVC = 4/10, p < 0.001). However, because the mean differences between genotype combinations were minor, the clinical roles of clock gene interactions are unlikely to be critical.

Genetic risk of Alzheimer’s disease is linked to short sleep duration

AbstractBackgroundSleep disturbances including short sleep duration are common in older adults, especially in those with Alzheimer’s disease (AD). However, it is unclear to what extent sleep duration is a manifestation of AD disease process. We examined whether genetic variants related to AD influence sleep duration in middle‐aged and older adults using a Mendelian randomization (MR) approach.MethodWe examined 406,687 UK Biobank participants without dementia at enrollment, with Caucasian genetic ancestry, and who self‐reported sleep duration at baseline (2006‐2010). Sleep duration was assessed by asking: “About how many hours sleep do you get in every 24 hours? (please include naps).” A genetic risk score for AD (AD‐GRS) was calculated as a weighted sum of 23 previously identified AD‐related single nucleotide polymorphisms in individuals of European ancestry. AD diagnosis was assessed over follow‐up (to 2018) based on ICD‐9/10 codes. We evaluated whether genetic risk for AD influenced sleep duration using two steps: first we used linear regression to examine the association between AD‐GRS and sleep duration, adjusting for age, sex and principle components for genetic ancestry. Next, we conducted a two‐stage least square regression using AD‐GRS as an instrumental variable for AD diagnosis to estimate the magnitude of the effect of AD on sleep duration. We also stratified the analysis by age at baseline (≤55y or &gt;55y).ResultParticipants (aged 56.91±8.00y) had an average sleep duration of 7.2 (Standard deviation [SD]=1.1) hours and AD‐GRS of 0.11 (SD=0.40; range:‐1.15∼1.85). Higher AD‐GRS score predicted shorter sleep duration (b= ‐0.013, 95%CI:‐0.022,‐0.005), mainly among those aged over 55y (b= ‐0.023, 95%CI:‐0.034,‐0.012) and not in those 55y or younger (b= 0.006, 95%CI:‐0.012,0.013); p for interaction by age=0.02. Analysis using AD‐GRS as an instrumental variable for AD diagnosis suggested that participants with AD diagnosis had 1.76 hrs (b=‐1.76, 95%CI: ‐2.62, ‐0.90) shorter sleep duration in those aged &gt;55y.ConclusionUsing a novel analytical approach, we found that higher genetic risk for AD predicted shorter sleep duration among older adults. This suggests shared genetic pathways; the biologic processes that lead to AD may also affect sleep duration.