A multi-cohort genome-wide association study in African ancestry individuals reveals risk loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG), the leading cause of irreversible blindness worldwide, disproportionately affects individuals of African ancestry. We conducted a genome-wide association study (GWAS) for POAG in 11,275 individuals of African ancestry (6,003 cases; 5,272 controls). We detected 46 risk loci associated with POAG at genome-wide significance. Replication and post-GWAS analyses, including functionally informed fine-mapping, multiple trait co-localization, and in silico validation, implicated two previously undescribed variants (rs1666698 mapping to DBF4P2; rs34957764 mapping to ROCK1P1) and one previously associated variant (rs11824032 mapping to ARHGEF12) as likely causal. For individuals of African ancestry, a polygenic risk score (PRS) for POAG from our mega-analysis (African ancestry individuals) outperformed a PRS from summary statistics of a much larger GWAS derived from European ancestry individuals. This study quantifies the genetic architecture similarities and differences between African and non-African ancestry populations for this blinding disease.

Genetics of reticular pseudodrusen in age-related macular degeneration.

Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.

Genetic susceptibility to acute viral bronchiolitis.

BACKGROUND: Acute viral bronchiolitis is a major cause of infant hospitalizations worldwide. Childhood bronchiolitis is considered a risk factor for asthma, suggesting shared genetic factors and biological pathways. Genetic risk loci may provide new insights into disease pathogenesis. METHODS: We conducted a genome-wide association study (GWAS) to examine the genetic contributions to bronchiolitis susceptibility in the FinnGen project data. We analyzed 1,465 infants hospitalized for bronchiolitis <2 years of age and 356,404 individuals without a history of acute lower respiratory infections (LRIs). RESULTS: GWAS identified associations (p<5×10-8) for variants in gasdermin B (GSDMB) and a missense variant in cadherin-related family member 3 (CDHR3). Children with bronchiolitis in infancy were more likely to develop asthma later in life compared to controls. The two associated loci were previously linked to asthma and susceptibility to wheezing illness by other causative agents than RSV. The identified loci associated with overall bronchiolitis, with larger effects in non-RSV than RSV-induced infection. CONCLUSION: Our results suggest that genetic variants in CDHR3 and GSDMB modulate susceptibility to bronchiolitis, especially when caused by viruses other than RSV. Severe bronchiolitis in infancy may trigger the development of asthma in genetically susceptible individuals, or it could be a marker of genetic predisposition to asthma.

Genome-wide association and Mendelian randomisation analysis among 30,699 Chinese pregnant women identifies novel genetic and molecular risk factors for gestational diabetes and glycaemic traits.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is the most common disorder in pregnancy; however, its underlying causes remain obscure. This study aimed to investigate the genetic and molecular risk factors contributing to GDM and glycaemic traits. METHODS: We collected non-invasive prenatal test (NIPT) sequencing data along with four glycaemic and 55 biochemical measurements from 30,699 pregnant women during a 2 year period at Shenzhen Baoan Women's and Children's Hospital in China. Genome-wide association studies (GWAS) were conducted between genotypes derived from NIPTs and GDM diagnosis, baseline glycaemic levels and glycaemic levels after glucose challenges. In total, 3317 women were diagnosed with GDM, while 19,565 served as control participants. The results were replicated using two independent cohorts. Additionally, we performed one-sample Mendelian randomisation to explore potential causal associations between the 55 biochemical measurements and risk of GDM and glycaemic levels. RESULTS: We identified four genetic loci significantly associated with GDM susceptibility. Among these, MTNR1B exhibited the highest significance (rs10830963-G, OR [95% CI] 1.57 [1.45, 1.70], p=4.42×10-29), although its effect on type 2 diabetes was modest. Furthermore, we found 31 genetic loci, including 14 novel loci, that were significantly associated with the four glycaemic traits. The replication rates of these associations with GDM, fasting plasma glucose levels and 0 h, 1 h and 2 h OGTT glucose levels were 4 out of 4, 6 out of 9, 10 out of 11, 5 out of 7 and 4 out of 4, respectively. Mendelian randomisation analysis suggested that a genetically regulated higher lymphocytes percentage and lower white blood cell count, neutrophil percentage and absolute neutrophil count were associated with elevated glucose levels and an increased risk of GDM. CONCLUSIONS/INTERPRETATION: Our findings provide new insights into the genetic basis of GDM and glycaemic traits during pregnancy in an East Asian population and highlight the potential role of inflammatory pathways in the aetiology of GDM and variations in glycaemic levels. DATA AVAILABILITY: Summary statistics for GDM; fasting plasma glucose; 0 h, 1 h and 2h OGTT; and the 55 biomarkers are available in the GWAS Atlas (study accession no.: GVP000001, https://ngdc.cncb.ac.cn/gwas/browse/GVP000001) .

Non-motor symptoms of Parkinson`s disease-insights from genetics.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor symptoms (NMS). NMS including sleep disturbances, depression, anxiety, and constipation are diverse, can precede motor symptoms, and significantly impact patients` quality of life. The severity and type of NMS vary based on age, disease severity, and motor symptoms, and while some respond to dopaminergic treatments, others may be induced or exacerbated by such treatments. NMS also play a role in differentiating PD from drug-induced parkinsonism and are related to gait dysfunction in both early and advanced stages. Genetic factors play a significant role in the development of NMS in PD, with mutations in genes such as SNCA, LRRK2, PRKN, and GBA being associated with severe and early NMS. Familial studies and identification of susceptibility factors have provided insights into the genetic underpinnings of NMS in PD. Neurobehavioral changes, including cognitive decline, are common NMS in PD, and their genetic basis involves a spectrum of mutations shared with other neurodegenerative disorders. Further research is needed to elucidate the functional implications of these genetic factors and their contributions to the pathogenesis of NMS in PD.

Maternal age and the risk of fetal aneuploidy: A nationwide cohort study of more than 500 000 singleton pregnancies in Denmark from 2008 to 2017.

INTRODUCTION: In this register-based study of pregnancies in Denmark, we assessed the associations between maternal age and the risk of fetal aneuploidies (trisomy 21, trisomy 18, trisomy 13, triploidy, monosomy X and other sex chromosome aberrations). Additionally, we aimed to disentangle the maternal age-related effect on fetal aneuploidies by cases with translocation trisomies and mosaicisms. MATERIAL AND METHODS: We followed a nationwide cohort of 542 375 singleton-pregnant women attending first trimester screening in Denmark between 2008 and 2017 until delivery, miscarriage or termination of pregnancy. We used six maternal age categories and retrieved information on genetically confirmed aneuploidies of the fetus and infant from the national cytogenetic register. RESULTS: We confirmed the known associations between advanced maternal age and higher risk of trisomy 21, 18, 13 and other sex chromosome aberrations, especially in women aged ≥35 years, whereas we found no age-related associations with triploidy or monosomy X. Cases with translocation trisomies and mosaicisms did not influence the overall reported association between maternal age and aneuploidies. CONCLUSION: This study provides insight into the accurate risk of fetal aneuploidies that pregnant women of advanced ages encounter.

Atopic Dermatitis: Disease Background and Risk Factors.

Multiple risk factors have been associated with the development of atopic dermatitis (AD). Recent advances in understanding the role of genetics in this disease have been made, with discovery of the filaggrin (FLG) gene as the most notable so far. In addition to FLG gene mutations as a risk factor for AD, a positive family history of atopic or allergic disease in either parent has been shown to confer a greater risk of developing AD. Atopic dermatitis usually presents early in life and is thought to represent the initial step in the "atopic march," which is characterized by the development of other atopic diseases later in life such as asthma, allergic rhinitis, and/or rhinoconjunctivitis, food allergies, and hay fever. Other comorbid diseases that have been associated with AD include increase risk of viral and bacterial skin infections, neuropsychiatric diseases such as attention-deficit hyperactivity disorders (ADHD), and autistic spectrum disorder (ASD). Patients with AD have also been found to have worse sleep quality overall compared to patients without AD. In this chapter, we will discuss the risk factors associated with development of atopic dermatitis as well as the most commonly reported comorbidities in patients with this disease.

Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high-incidence country.

Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population-based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non-genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision-recall curve (AUC-PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC-PRC for the Baseline Model (0.44%, 95%CI 0.42-0.46) increased by 0.22 (95%CI 0.15-0.29) when non-genetic factors were included, and by 0.25 (95%CI 0.20-0.30) when incorporating non-genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104-131) decreased to 92 (95%CI 60-128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59-110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non-genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.

Estrogen receptor alpha (ESR1) gene polymorphism (rs2234693 and rs2046210) with breast cancer risk in pashtun population of Khyber Pakhtunkhwa.

BACKGROUND: Breast cancer susceptibility is greatly influenced by single nucleotide polymorphisms (SNPs) both in penetrance and non-penetrance genes. The Estrogen Receptor Alfa (ESR1- rs2234693 and rs2046210) have been reported as risk factor of breast cancer in different ethnic groups with inconsistent results. In this study the association of ESR1 (rs2234693 and rs2046210) with breast cancer risk was investigated in patients of Khyber Pakhtunkhwa. METHODS: A total of 312 females including 162 breast cancer patients and 150 healthy controls were enrolled in this study. The polymorphism was confirmed using T-ARMS-PCR. RESULTS: Our results revealed that ESR1-rs2234693 risk allele (C) (P = 0.21, OR = 1.27, CI = 0.87 to 1.87) and containing genotypes CC (P = 0.68, OR = 1.24, CI = 0.42 to 3.68) and TC (P = 0.23, OR = 1.32, CI = 0.83 to 2.13) were not associated with the risk of breast cancer. In case of rs2046210, the risk allele A (P < 0.0001, OR = 2.42, CI = 1.74 to 3.38) and corresponding genotypes GA (P = 0.0001, OR = 2.55, CI = 1.62 to 4.03) and AA (P = 0.02, OR = 2.20, CI = 1.12 to 4.34) were significantly associated with higher risk of breast cancer. Moreover, ESR1-rs2234693 was significantly (P < 0.05) associated with family history, stages, PR status, ER status and luminal B. The ESR1-rs2046210 showed significant (P ≤ 0.05) association with menstrual status, tumor grade and TNBC. Both the SNPs showed non-significant (P > 0.05) association with nulliparity, nodal status, HER2 status, metastasis, HER2 enriched subtype and luminal A. CONCLUSION: It is concluded that ESR1-rs2234693 is not associated with breast cancer, while rs2046210 is significantly associated with the risk of breast cancer in Khyber Pakhtunkhwa population. Further, to confirm the exact situation of ESR1 polymorphism, ESR1 existing and other SNPs need to be investigated in diverse data sets.

A Comprehensive Investigation on Potential Risk Factors for NSCL/P in a Rural District of Hebei Province, China.

Non syndromic cleft lip with or without palate (NSCL/P), one of the most common birth defects, is closely related to various risk factors. However, information regarding risk factors for NSCL/P in rural districts in China is very limited thus far. The objective of this study was designed to identify the potential risk factors for NSCL/P in rural districts.A comprehensive retrospective investigation including 435 NSCL/P patients and 402 healthy children was carried out in Hebei Province, China. Multiple logistic regression analysis and transmission disequilibrium test (TDT) were respectively used to identify non-genetic and genetic risk factors for NSCL/P, and then PLINK was used to explore the relationship between non-genetic and genetic risk factors.The results showed that maternal periconceptional exposure to pesticides and herbicides, as well as low parental education level were involved in the increased risk of NSCL/P, whereas maternal folic acid and multivitamin supplementation use during preconception period were associated with the reduced risk of NSCL/P. TDT analysis identified 2 single nucleotide polymorphisms (SNPs) (rs7078160 and rs4752028) in VAX1 and one SNP (rs17563) in BMP4 as the genetic risk factors for NSCL/P. Further analysis showed that the genetic risk factors were closely related with the negative non-genetic risk factors.Our study identified the potential risk factors for NSCL/P in rural districts, thus providing a theoretical basis for the prevention of NSCL/P occurrence.

Risk score prediction model based on single nucleotide polymorphism for predicting malaria: a machine learning approach.

BACKGROUND: The malaria risk prediction is currently limited to using advanced statistical methods, such as time series and cluster analysis on epidemiological data. Nevertheless, machine learning models have been explored to study the complexity of malaria through blood smear images and environmental data. However, to the best of our knowledge, no study analyses the contribution of Single Nucleotide Polymorphisms (SNPs) to malaria using a machine learning model. More specifically, this study aims to quantify an individual's susceptibility to the development of malaria by using risk scores obtained from the cumulative effects of SNPs, known as weighted genetic risk scores (wGRS). RESULTS: We proposed an SNP-based feature extraction algorithm that incorporates the susceptibility information of an individual to malaria to generate the feature set. However, it can become computationally expensive for a machine learning model to learn from many SNPs. Therefore, we reduced the feature set by employing the Logistic Regression and Recursive Feature Elimination (LR-RFE) method to select SNPs that improve the efficacy of our model. Next, we calculated the wGRS of the selected feature set, which is used as the model's target variables. Moreover, to compare the performance of the wGRS-only model, we calculated and evaluated the combination of wGRS with genotype frequency (wGRS + GF). Finally, Light Gradient Boosting Machine (LightGBM), eXtreme Gradient Boosting (XGBoost), and Ridge regression algorithms are utilized to establish the machine learning models for malaria risk prediction. CONCLUSIONS: Our proposed approach identified SNP rs334 as the most contributing feature with an importance score of 6.224 compared to the baseline, with an importance score of 1.1314. This is an important result as prior studies have proven that rs334 is a major genetic risk factor for malaria. The analysis and comparison of the three machine learning models demonstrated that LightGBM achieves the highest model performance with a Mean Absolute Error (MAE) score of 0.0373. Furthermore, based on wGRS + GF, all models performed significantly better than wGRS alone, in which LightGBM obtained the best performance (0.0033 MAE score).

Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM.

BACKGROUND: Multigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene. METHODS: We included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case-control-family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis. RESULTS: The estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45-3.87; P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6-30). CONCLUSIONS: Although ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

Assessment of evidence on reported non-genetic risk factors of congenital heart defects: the updated umbrella review.

BACKGROUND: Congenital heart defect (CHD) is the leading cause of birth defects globally, which results in a great disease burden. It is still imperative to detect the risk factors of CHD. This umbrella review aimed to comprehensively summarize the evidence and grade the evidence of the associations between non-genetic risk factors and CHD. METHODS: Databases including Medline, Embase, Web of Science, Cochrane Library, and four Chinese databases were searched from inception to 18 Jan 2022. The reference lists of systematic reviews (SR) and meta-analyses (MA) were screened, which aimed to explore the non-genetic risk factors of CHD. Subsequently, titles and abstracts of identified records and full texts of selected SR/MA were screened by two independent reviewers based on predefined eligibility criteria. A priori developed extraction form was used to abstract relative data following the PRISMA 2020 and MOOSE guidelines. The risk of bias was assessed with the AMSTAR2 instrument. Data were synthesized using fixed-effects and random-effects meta-analyses, respectively. Finally, the evidence on the association of non-genetic risk factors and CHD was graded using Ioannidis's five-class evidence grade. RESULTS: A total of 56 SRs, encompassing 369 MAs, were identified. The risk factors included relative factors on air pollution, reproductive-related factors, parental age and BMI, parental life habits, working and dwelling environment, maternal drug exposure, and maternal disease. Based on AMSTAR2 criteria, only 16% (9/56) of SRs were classified as "Moderate". One hundred and two traceable positive association MAs involving 949 component individual studies were included in further analysis and grading of evidence. Family genetic history, number of abortions, maternal obesity, especially moderate or severe obesity, decoration materials, harmful chemicals, noise during pregnancy, folic acid supplementation, SSRIs, SNRIs, any antidepressants in the first trimester, maternal DM (including both PGDM and GDM), and gestational hypertension were convincing and highly suggestive factors for CHD. After sensitivity analyses based on cohort studies, some grades of evidence changed. CONCLUSION: The present umbrella review will provide evidence-based information for women of childbearing age before or during pregnancy to prevent CHD. In addition, sensitivity analysis based on cohort studies showed the changed evidence levels. Therefore, future SR/MA should concern the sensitivity analysis based on prospective birth cohort studies and case-control studies.

The Genetic Architecture of the Etiology of Lower Extremity Peripheral Artery Disease: Current Knowledge and Future Challenges in the Era of Genomic Medicine.

Lower extremity artery disease (LEAD), caused by atherosclerotic obstruction of the arteries of the lower limb extremities, has exhibited an increase in mortality and morbidity worldwide. The phenotypic variability of LEAD is correlated with its complex, multifactorial etiology. In addition to traditional risk factors, it has been shown that the interaction between genetic factors (epistasis) or between genes and the environment potentially have an independent role in the development and progression of LEAD. In recent years, progress has been made in identifying genetic variants associated with LEAD, by Genome-Wide Association Studies (GWAS), Whole Exome Sequencing (WES) studies, and epigenetic profiling. The aim of this review is to present the current knowledge about the genetic factors involved in the etiopathogenic mechanisms of LEAD, as well as possible directions for future research. We analyzed data from the literature, starting with candidate gene-based association studies, and then continuing with extensive association studies, such as GWAS and WES. The results of these studies showed that the genetic architecture of LEAD is extremely heterogeneous. In the future, the identification of new genetic factors will allow for the development of targeted molecular therapies, and the use of polygenic risk scores (PRS) to identify individuals at an increased risk of LEAD will allow for early prophylactic measures and personalized therapy to improve their prognosis.

Clarifying the Trade-Offs of Risk-Stratified Screening for Prostate Cancer: A Cost-Effectiveness Study.

Cancer risk prediction is necessary for precision early detection, which matches screening intensity to risk. However, practical steps for translating risk predictions to risk-stratified screening policies are not well established. We used a validated population prostate-cancer model to simulate the outcomes of strategies that increase intensity for men at high risk and reduce intensity for men at low risk. We defined risk by the Prompt Prostate Genetic Score (PGS) (Stratify Genomics, San Diego, California), a germline genetic test. We first recalibrated the model to reflect the disease incidence observed within risk strata using data from a large prevention trial where some participants were tested with Prompt PGS. We then simulated risk-stratified strategies in a population with the same risk distribution as the trial and evaluated the cost-effectiveness of risk-stratified screening versus universal (risk-agnostic) screening. Prompt PGS risk-adapted screening was more cost-effective when universal screening was conservative. Risk-stratified strategies improved outcomes at a cost of less than $100,000 per quality-adjusted life year compared with biennial screening starting at age 55 years, but risk stratification was not cost-effective compared with biennial screening starting at age 45. Heterogeneity of risk and fraction of the population within each stratum were also important determinants of cost-effectiveness.

Association of BST1 polymorphism with idiopathic restless legs syndrome in Chinese population.

BACKGROUND: Parkinson's disease (PD) and restless legs syndrome/Willis-Ekbom disease (RLS/WED) are both common movement disorders. Based on their clinical overlap, association studies of PD and RLS/WED have been conducted for many years. OBJECTIVE: To investigate whether or not the genetic risk factor of PD was also associated with RLS/WED. SUBJECTS AND METHODS: We included 102 idiopathic RLS/WED patients and 189 matched controls from southeast China. The clinical data included the International Restless Legs Syndrome Study Group Rating Scale, the subtypes of RLS/WED symptoms (painful or other discomfort), the comorbidities, the pregnancy history of female patients, the Hamilton Depression Scale (HAMD), and the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Risk gene analysis between RLS/WED and control groups including 21 SNPs (single nucleotide polymorphisms) was conducted. Genotyping was done by Sanger sequencing. RESULTS: We found that rs4273468 polymorphism of BST1 gene increased the risk of idiopathic RLS/WED patients in southeastern Chinese population (P = <0.001, OR = 2.85, p = 0.019 after Bonferroni correction). Moreover, the haplotype of G-G (rs4698412-rs4273468) was significantly associated with Chinese RLS/WED patients (p = <0.001). CONCLUSION: BST1 may contribute to the development of RLS/WED. Further studies on larger cohorts are needed to confirm these findings.

Current Knowledge of Asthma-COPD Overlap (ACO) Genetic Risk Factors, Characteristics, and Prognosis.

Asthma-COPD overlap (ACO) is a newly identified phenotype of chronic obstructive airway diseases with shared asthma and COPD features. Patients with ACO are poorly defined, and some evidence suggests that they have worse health outcomes and greater disease burden than patients with COPD or asthma. Generally, there is no evidence-based and universal definition for ACO; several consensus documents have provided various descriptions of the phenotype. In addition, the mechanisms underlying the development of ACO are not fully understood. Whether ACO is a distinct clinical entity with its particular discrete genetic determinant different from asthma and COPD alone or an intermediate phenotype with overlapping genetic markers within asthma and COPD spectrum of obstructive airway disease remains unproven. This review summarizes the current knowledge of the genetic risk factors, characteristics, and prognosis of ACO.

[The IMAGEN cohort: perspectives and problems of longitudinal research]. / Die IMAGEN-Kohorte: Perspektiven und Probleme longitudinaler Forschung.

BACKGROUND: Genetic risk factors for major mental disorders identified in psychiatric research show a substantial overlap. Therefore, it has been suggested that neurobiological research should focus on intermediate phenotypes that reflect shared aspects of different mental disorders due to overlapping genetic effects and environmental factors. Longitudinal studies are required to assess the interaction between genetic variability and modifying environmental factors and to investigate the effects on intermediate phenotypes and (mediated by them) on the expression of individual mental disorders. OBJECTIVE: Discussion of the possibilities and limitations of longitudinal cohort studies using the IMAGEN study as an example. MATERIAL AND METHODS: The results of the European IMAGEN study are presented with a focus on addiction. RESULTS: The longitudinal assessments of the IMAGEN cohort revealed that neuroimaging data indicating a low activation of the dopaminergic reinforcement system detected at the age of 14 years are predictive for increased drug use. In addition to genetic factors, environmental influences such as maternal smoking during pregnancy were correlated with this low activation. CONCLUSION: Longitudinal neurobiological basic research can validate the effects of candidate genes and reveal relevant environmental factors. Relevant modifiable factors indicated by the IMAGEN study and related datasets include drug use during pregnancy, trauma and other experiences of violence, social disadvantage and exclusion.

Assessment of the FAM174A 11G allele as a risk allele for equine metabolic syndrome.

An 11G nucleotide repeat in the 3' UTR of FAM174A was recently postulated as a risk allele with a dominant mode of inheritance for equine metabolic syndrome (EMS) and laminitis status in Arabian horses. The objective of this project was to evaluate this hypothesis in a large and diverse across-breed population. A total of 301 ponies, 292 Morgans, 64 Arabians, 49 Tennessee Walking Horses and 59 Quarter Horses were genotyped for six observed G repeat alleles in the FAM174A 3' UTR. Phenotype data included laminitis status, baseline insulin, glucose, non-esterified fatty acids, triglycerides, adiponectin, leptin, ACTH, insulin and glucose post oral sugar test, and two proxies for insulin resistance. The 11G allele frequencies were 18.8, 6.9, 1.8, 0.2 and 0.0% in the Arabians, Tennessee Walkers, ponies, Morgans and Quarter Horses respectively. Association analyses between FAM174A genotype and EMS phenotypes, and between allele count and EMS phenotypes, identified no statistically significant associations. When a dominant effect for the 11G allele was evaluated, a statistically significant association with adiponectin levels was identified in the ponies, and pairwise comparisons revealed that the estimated marginal means were higher in ponies with the 11G allele vs. alternative alleles (i.e. the allele had a protective effect). In conclusion, our data do not support the FAM174A 11G allele as a risk allele for EMS in our studied breeds.

Should Genetics Now Be Considered the Pre-eminent Etiologic Factor in Endometriosis?

Endometriosis is a common, estrogen-dependent, inflammatory disorder characterized by the growth of endometrial-like tissue at extrauterine locations. Its pathogenesis and mechanisms underlying its pathophysiology are poorly understood, although genetic variation is strongly implicated in these processes. Genetic studies reveal that approximately 50% of risk for endometriosis is due to genetic factors and the other 50% likely owing to environmental factors. As with other complex diseases, genetic variants in the DNA sequence increasing endometriosis risk all have small effects, unlike most single-gene disorders. It is the combinations of these variants adding together that contribute to higher risks for individual women. In addition, recent data on disease lesions demonstrate a high frequency of somatic (likely acquired) mutations, some of which are present in the eutopic endometrium and specifically in the epithelial cell compartment, raising the possibility that abnormal epithelial progenitors in the eutopic endometrium give rise to ectopic disease. Discovery in this field is occurring at a rapid pace, and further definitions of genetic (germline) and environmental (somatic) contributions to the pathogenesis and pathophysiology of this disorder are anticipated soon. These discoveries are expected to increase diagnostic, therapeutic, and preventive strategies to minimize disease and its associated morbidities.