Evaluating shared genetic influences on nonsyndromic cleft lip/palate and oropharyngeal neoplasms

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.     

iFunMed: Integrative functional mediation analysis of GWAS and eQTL studies

Genome-wide association studies (GWAS) have successfully identified thousands of genetic variants contributing to disease and other phenotypes. However, significant obstacles hamper our ability to elucidate causal variants, identify genes affected by causal variants, and characterize the mechanisms by which genotypes influence phenotypes. The increasing availability of genome-wide functional annotation data is providing unique opportunities to incorporate prior information into the analysis of GWAS to better understand the impact of variants on disease etiology. Although there have been many advances in incorporating prior information into prioritization of trait-associated variants in GWAS, functional annotation data have played a secondary role in the joint analysis of GWAS and molecular (i.e., expression) quantitative trait loci (eQTL) data in assessing evidence for association. To address this, we develop a novel mediation framework, iFunMed, to integrate GWAS and eQTL data with the utilization of publicly available functional annotation data. iFunMed extends the scope of standard mediation analysis by incorporating information from multiple genetic variants at a time and leveraging variant-level summary statistics. Data-driven computational experiments convey how informative annotations improve single-nucleotide polymorphism (SNP) selection performance while emphasizing robustness of iFunMed to noninformative annotations. Application to Framingham Heart Study data indicates that iFunMed is able to boost detection of SNPs with mediation effects that can be attributed to regulatory mechanisms.     

Transforming growth factor α locus and nonsyndromic cleft lip with or without cleft palate: A reappraisal

An association between nonsyndromic cleft lip with or without cleft palate (CL±P) and genetic variation at the transforming growth factor α (TGFA) locus was originally reported in 1989. Subsequent population-based studies of this association have provided conflicting results. The present analyses were undertaken to determine if the cumulative weight of the available data convincingly supports or refutes this association. The published data were analyzed for differences in allele frequencies between Caucasian CL±P patients (i.e., cases) and controls, and for heterogeneity between Caucasian samples. When all data except the original report were considered, there was a statistically significant association between TGFA and CL±P (M.H.O.R. = 1.43; 95% C.I. 1.12–1.80). However, there was evidence of significant heterogeneity in the TGFA allele frequencies between cases, but not controls, from different studies. The data suggest that the observed heterogeneity is unlikely to be attributable to differences in the ethnic composition of the cases among the various studies but may reflect differences in the proportion of cases with bilateral lip defects and/or with positive family histories of CL±P. Definitive conclusions regarding the source(s) of the observed heterogeneity could not, however, be drawn on the basis of the available data. Hence, at present, the evidence regarding an association between genetic variation at the TGFA locus and CL±P remains inconclusive. Genet. Epidemiol. 14:231–240,1997. © 1997 Wiley-Liss, Inc.     

Spinning convincing stories for both true and false association signals

When interpreting genome-wide association peaks, it is common to annotate each peak by searching for genes with plausible relationships to the trait. However, “all that glitters is not gold”—one might interpret apparent patterns in the data as plausible even when the peak is a false positive. Accordingly, we sought to see how human annotators interpreted association results containing a mixture of peaks from both the original trait and a genetically uncorrelated “synthetic” trait. Two of us prepared a mix of original and synthetic peaks of three significance categories from five different scans along with relevant literature search results and then we all annotated these regions. Three annotators also scored the strength of evidence connecting each peak to the scanned trait and the likelihood of further studying that region. While annotators found original peaks to have stronger evidence (p _Bonferroni = 0.017) and higher likelihood of further study ( p _Bonferroni = 0.006) than synthetic peaks, annotators often made convincing connections between the synthetic peaks and the original trait, finding these connections 55% of the time. These results show that it is not difficult for annotators to make convincing connections between synthetic association signals and genes found in those regions.     

Common genetic variants have associations with human cortical brain regions and risk of schizophrenia

Schizophrenia is a highly heritable mental disorder and is reported to be associated with measurements in cortical regions of the human brain. In this study, we considered genome-wide association studies to uncover genetic effects on cortical regions and prodromal symptoms of schizophrenia. Specifically, area, thickness, and volume of 66 cortical regions derived from magnetic resonance imaging scans of 1,445 children and adolescents from the Philadelphia Neurodevelopmental Cohort were studied. Two common variants were identified as being associated with two prefrontal cortical regions (one significant variant rs11601331 on chromosome 11p11 for right rostral middle frontal gyral area, p = 1.97 × 10 ⁻⁸; one suggestive variant rs2345981 on chromosome 6q11 for left frontal pole gyral volume, p = 2.07 × 10 ⁻⁷), where the significance of rs11601331 was independently replicated on the Pediatric Imaging, Neurocognition, and Genetics study of size 1,239 (p = 9.19 × 10 ⁻³). Moreover, genetic effects on schizophrenia were investigated based on a sample of 8,719 subjects. The two identified variants rs11601331 and rs2345981 showed significant association with the longest prodromal symptoms duration (p = 0.048 and p = 0.027, respectively).     

On the differences between mega- and meta-imputation and analysis exemplified on the genetics of age-related macular degeneration

While current genome-wide association analyses often rely on meta-analysis of study-specific summary statistics, individual participant data (IPD) from multiple studies increase options for modeling. When multistudy IPD is available, however, it is unclear whether this data is to be imputed and modeled across all participants (mega-imputation and mega-analysis) or study-specifically (meta-imputation and meta-analysis). Here, we investigated different approaches toward imputation and analysis using 52,189 subjects from 25 studies of the International Age-related Macular Degeneration (AMD) Genomics Consortium including, 16,144 AMD cases and 17,832 controls for association analysis. From 27,448,454 genetic variants after 1,000-Genomes-based imputation, mega-imputation yielded ~400,000 more variants with high imputation quality (mostly rare variants) compared to meta-imputation. For AMD signal detection (P < 5 × 10⁻⁸) in mega-imputed data, most loci were detected with mega-analysis without adjusting for study membership (40 loci, including 34 known); we considered these loci genuine, since genetic effects and P-values were comparable across analyses. In meta-imputed data, we found 31 additional signals, mostly near chromosome tails or reference panel gaps, which disappeared after accounting for interaction of whole-genome amplification (WGA) with study membership or after excluding studies with WGA-participants. For signal detection with multistudy IPD, we recommend mega-imputation and mega-analysis, with meta-imputation followed by meta-analysis being a computationally appealing alternative.     

Ordered multinomial regression for genetic association analysis of ordinal phenotypes at Biobank scale

Logistic regression is the primary analysis tool for binary traits in genome-wide association studies (GWAS). Multinomial regression extends logistic regression to multiple categories. However, many phenotypes more naturally take ordered, discrete values. Examples include (a) subtypes defined from multiple sources of clinical information and (b) derived phenotypes generated by specific phenotyping algorithms for electronic health records (EHR). GWAS of ordinal traits have been problematic. Dichotomizing can lead to a range of arbitrary cutoff values, generating inconsistent, hard to interpret results. Using multinomial regression ignores trait value hierarchy and potentially loses power. Treating ordinal data as quantitative can lead to misleading inference. To address these issues, we analyze ordinal traits with an ordered, multinomial model. This approach increases power and leads to more interpretable results. We derive efficient algorithms for computing test statistics, making ordinal trait GWAS computationally practical for Biobank scale data. Our method is available as a Julia package OrdinalGWAS.jl. Application to a COPDGene study confirms previously found signals based on binary case–control status, but with more significance. Additionally, we demonstrate the capability of our package to run on UK Biobank data by analyzing hypertension as an ordinal trait.     

A variance components factor model for genetic association studies: A Bayesian analysis

Studies of gene‐trait associations for complex diseases often involve multiple traits that may vary by genotype groups or patterns. Such traits are usually manifestations of lower‐dimensional latent factors or disease syndromes. We illustrate the use of a variance components factor (VCF) model to model the association between multiple traits and genotype groups as well as any other existing patient‐level covariates. This model characterizes the correlations between traits as underlying latent factors that can be used in clinical decision‐making. We apply it within the Bayesian framework and provide a straightforward implementation using the WinBUGS software. The VCF model is illustrated with simulated data and an example that comprises changes in plasma lipid measurements of patients who were treated with statins to lower low‐density lipoprotein cholesterol, and polymorphisms from the apolipoprotein‐E gene. The simulation shows that this model clearly characterizes existing multiple trait manifestations across genotype groups where individuals' group assignments are fully observed or can be deduced from the observed data. It also allows one to investigate covariate by genotype group interactions that may explain the variability in the traits. The flexibility to characterize such multiple trait manifestations makes the VCF model more desirable than the univariate variance components model, which is applied to each trait separately. The Bayesian framework offers a flexible approach that allows one to incorporate prior information. Genet. Epidemiol. 34: 529–536, 2010. © 2010 Wiley‐Liss, Inc.     

A better coefficient of determination for genetic profile analysis

Genome-wide association studies have facilitated the construction of risk predictors for disease from multiple Single Nucleotide Polymorphism markers. The ability of such "genetic profiles" to predict outcome is usually quantified in an independent data set. Coefficients of determination (R(2) ) have been a useful measure to quantify the goodness-of-fit of the genetic profile. Various pseudo-R(2) measures for binary responses have been proposed. However, there is no standard or consensus measure because the concept of residual variance is not easily defined on the observed probability scale. Unlike other nongenetic predictors such as environmental exposure, there is prior information on genetic predictors because for most traits there are estimates of the proportion of variation in risk in the population due to all genetic factors, the heritability. It is this useful ability to benchmark that makes the choice of a measure of goodness-of-fit in genetic profiling different from that of nongenetic predictors. In this study, we use a liability threshold model to establish the relationship between the observed probability scale and underlying liability scale in measuring R(2) for binary responses. We show that currently used R(2) measures are difficult to interpret, biased by ascertainment, and not comparable to heritability. We suggest a novel and globally standard measure of R(2) that is interpretable on the liability scale. Furthermore, even when using ascertained case-control studies that are typical in human disease studies, we can obtain an R(2) measure on the liability scale that can be compared directly to heritability.     

Genetics of Type 2 Diabetes: Past,Present, and Future

Diabetes has reached epidemic proportions worldwide. Currently, approximately 537 million adults (20–79 years) have diabetes, and the total number of people with diabetes is continuously increasing. Diabetes includes several subtypes. About 80% of all cases of diabetes are type 2 diabetes (T2D). T2D is a polygenic disease with an inheritance ranging from 30 to 70%. Genetic and environment/lifestyle factors, especially obesity and sedentary lifestyle, increase the risk of T2D. In this review, we discuss how studies on the genetics of diabetes started, how they expanded when genome-wide association studies and exome and whole-genome sequencing became available, and the current challenges in genetic studies of diabetes. T2D is heterogeneous with respect to clinical presentation, disease course, and response to treatment, and has several subgroups which differ in pathophysiology and risk of micro- and macrovascular complications. Currently, genetic studies of T2D focus on these subgroups to find the best diagnoses and treatments for these patients according to the principles of precision medicine.     

出生缺陷的遗传和/或环境因素的最新研究进展

出生缺陷是指胚胎由于染色体畸变、基因突变等遗传原因,或者物理、化学、生物等环境原因,或二者的交互作用所引起的先天性异常。导致出生缺陷的因素不论从环境因素、还是遗传因素等研究进展迅速,本文系统介绍出生缺陷的影响因素及其最新研究结果和主要观点,以期对出生缺陷原因有更全面的了解,进一步提出有针对性的预防干预措施。     

Congenital anomalies among the offspring of fire fighters

A case-control study has been conducted to determine the association between employment as a fire fighter and congenital heart defects among the offspring. Cases were fathers of all children born between 1979 and 1986 in Ontario, Canada, who were diagnosed with a cardiac congenital anomaly during the first year of life (n = 9340). Matched controls (n = 9340), defined as fathers whose child did not have a congenital anomaly, were randomly selected from the Ontario birth certificate file. In order to identify those fathers who had been employed as a fire fighter, the cases and controls were linked to a cohort of Metropolitan Toronto fire fighters. Eleven cases and nine controls worked as fire fighters, giving an odds ratio of 1.22 (95 percent confidence interval 0.46–3.33). This study had sufficient power to detect the level of risk reported in one previous study; however, these results do not support a hypothesis of elevated risk of cardiac congenital anomalies among the offspring of fire fighters. © 1996 Wiley-Liss, Inc.     

Test of genetic heterogeneity of cleft lip with or without cleft palate as related to race and severity

The question of possible heterogeneity among population groups and phenotypic groups on the role of major gene in the etiology of cleft lip with or without cleft palate [CL(P)] was examined using the uniformly collected data in Hawaii. Complex segregation analysis was used to analyze patterns of family resemblance under the mixed model incorporating the effects of major gene and multifactorial inheritance. Analysis of the entire data showed superior fit of the mixed model including the effects of both major gene and multifactorial inheritance over the model of major gene alone or multifactorial inheritance alone. No significant heterogeneity could be detected between the high-incidence group (Oriental or Japanese) and the low-incidence group (non-Oriental) in the underlying general model, although higher heritability was observed in general. When families were classified into "severe" and "mild" phenotypes based on cleft lip vs. cleft lip and palate or unilateral vs. bilateral cleft in the proband, no significant differences could be detected between the two types in the underlying genetic model.     

Exome chip-driven association study of lipidemia in >14,000 Koreans and evaluation of genetic effect on identified variants between different ethnic groups

Lipid levels in blood are widely used to diagnose and monitor chronic diseases. It is essential to identify the genetic traits involved in lipid metabolism for understanding chronic diseases. However, the influence of genetic traits varies depending on race, sex, age, and ethnicity. Therefore, research focusing on populations of individual countries is required, and the results can be used as a basis for comparison of results of other studies at the cross-racial and cross-country levels. In the present study, we selected lipid-related variants and evaluated their effects on lipid-related diseases in more than 14,000 subjects of three cohorts using the Illumina Human Exome Beadchip. A genome-wide association study was conducted using EPACTs after adjusting for age, sex, and recruitment area. A genome-wide significance cutoff was defined as p < 5E−08 in all the three cohorts. Sixteen variants represented the lipid traits and were classified as vulnerable to borderline hypertriglyceridemia, hyper-LDL-cholesterolemia, or hypo-HDL-cholesterolemia. Moreover, we compared the genetic effects of the 16 variants between ethnic groups and identified the missense variants in apolipoprotein A-V, cholesterol ester transfer protein, and apolipoprotein E as Asian-specific. Our study provides candidate genes as markers for chronic diseases through the evaluation of genetic effects.     

围产儿1 502 020例出生缺陷监测结果分析

目的 分析围产儿出生缺陷情况,了解其动态变化,进一步做好出生缺陷防控工作。方法 对吉林省2002-2011年监测医院出生的孕28周至生后7 d的1 502 020例围产儿按照国家出生缺陷监测方案进行监测。结果 共监测1 502 020例围产儿,缺陷儿11 892例,出生缺陷总发生率为79.17/10⁴,主要缺陷类型是先天性心脏病、总唇裂、多指(趾)、先天性脑积水、神经管缺陷。农村和城镇地区的出生缺陷发生率分别为70.01/10⁴和89.72/10⁴。男性和女性围产儿的出生缺陷发生率分别为84.89/10⁴和71.04/10⁴。母亲年龄20岁以下缺陷儿的发生率最高,35岁以上次之。先天性心脏病发生率从2002年的5.61/10⁴上升至2011年的13.67/10⁴,多指(趾)发生率从2002年的5.75/10⁴升高至2011年的11.69/10⁴,神经管缺陷发生率从2002年的8.40/10⁴下降至2011年的3.47/10⁴。结论 吉林省近10年神经管缺陷和总唇裂发生率降低明显,先天性心脏病和多指(趾)发生率升高明显。深入研究出生缺陷致畸因素,普及健康教育,加强三级预防措施,降低出生缺陷发生水平,做好优生优育工作。     

Association of Parental Environmental Exposures and Supplementation Intake with Risk of Nonsyndromic Orofacial Clefts: A Case-Control Study in Heilongjiang Province,China

The aim of present study was to check the possible association of potential parental environmental exposures and maternal supplementation intake with the risk of nonsyndromic orofacial clefting (NSOC). A retrospective study comprised 499 cases and 480 controls was conducted in Heilongjiang Province. Chi-square analysis and unconditional multiple logistic regression were used in the study. The results showed that maternal history of fever and the common cold without fever (OR_CL/P = 3.11 and 5.56, 95%CI: 1.67–5.82 and 2.96–10.47, OR_CPO = 3.31 and 8.23, 95%CI: 1.58–6.94 and 4.08–16.95), paternal smoking and alcohol consumption (OR_CL/P = 2.15 and 5.04, 95%CI: 1.37–3.38 and 3.00–8.46, OR_CPO = 1.82 and 4.40, 95%CI: 1.06–3.13 and 2.50–7.74), maternal exposure to organic solvents, heavy metals, or pesticides (OR_CL/P = 6.07, 5.67 and 5.97, 95%CI: 1.49–24.76, 1.34–24.09 and 2.10–16.98, OR_CPO = 10.65, 7.28 and 3.48, 95%CI: 2.54–44.67, 1.41–37.63 and 1.06–11.46) and multivitamin use during the preconception period (OR_CL/P = 0.06, 95%CI: 0.02–0.23, OR_CPO = 0.06, 95%CI: 0.01–0.30) were associated with cleft lip or without cleft palate (CL/P) and cleft palate only (CPO). Maternal history of skin disease and negative life events (OR_CL/P = 12.07 and 1.67, 95%CI: 1.81–80.05 and 1.95–2.67) were associated with CL/P. Some potential parental hazardous exposures during the periconception period and maternal use of multivitamins during the preconception period were associated with risk of NSOC.     

Variants of developmental genes (TGFA,TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis

We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL+/-P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL+/-P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32) among children homozygous for both the MSX1-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL+/-P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSX1-CA A4 allele, raising the possibility of interaction between these two genes.     

1204名已婚护士妊娠结局调查与分析

目的了解护士妊娠结局情况,为采取保护护士生殖健康的干预措施提供参考依据。方法采用整群抽样的方法 ,随机抽取北京市2家三级综合医院和1家肿瘤医院的1 204名已婚护士,通过护士生殖健康状况调查问卷,调查护士妊娠结局的情况。结果护士所生孩子早产率、死产率在各医院和各科室之间没有统计学差异(x^2值分别为0.06、2.21、4.50、11.96,均P>0.05),而护士的自然流产发生率在各医院和各科室间有统计学差异(x^2值分别为14.71、14.18,均P<0.05),肿瘤医院护士自然流产率高于综合医院,ICU护士自然流产率高于其他科室,护士自然流产发生率为14.20%。护士所生孩子出生缺陷率为17.20‰,各医院护士所生孩子的出生缺陷率差异无统计学意义(x^2=0.22,P>0.05),各医院与北京市出生缺陷率的差异无统计学意义(x^2值分别为2.54、0.02、2.00,均P>0.05)。护士所生孩子死亡率为4.04‰,肿瘤医院护士所生孩子的新生儿死亡率是北京市新生儿死亡率的4倍,其差异有统计学意义(x^2=4.09,P<0.05)。结论肿瘤医院护士妊娠期自然流产发生率高于综合医院护士的自然流产率,肿瘤医院护士所生孩子的新生儿死亡率较高,需进一步对肿瘤医院护士职业卫生防护状况开展深入的调查研究。     

An epidemiological study of work with video screens and pregnancy outcome: I. A registry study

Three cohorts of women were identified with the aid of occupational codes in the census, linked to the Medical Birth Registry and an Inpatient Registry, containing information on women hospitalized for spontaneous abortion. The three cohorts were selected from the same socioeconomic stratum but had different probabilities to be exposed for video screen work: high, medium, and low. The total pregnancy outcome of the three groups of women did not differ significantly, but there was a weak trend for more spontaneous abortions and perhaps also for congenital malformations in the group with the highest video screen work exposure; however, the differences could be random. Comparisons of delivery outcomes for these cohorts in 1976-77 with those in 1980-81 did not show any consistent pattern in spite of the heavy computerization of these workplaces which occurred between the two time periods. The second part of this report studies the material in further detail.