Results Of Genetic Association Studies Research Articles

Gene‐level Association Study of Alzheimer’s Disease on CHS and FRAM cohorts

AbstractBackgroundExperimental, clinical, and genetic epidemiological studies continue clarifying important aspects of Alzheimer’s disease (AD) pathological development. Despite this progress the genetic mechanisms of AD regulation remain unclear. One problem that may contribute to slowing further progress in better understanding of these mechanisms deals with difficulties in replication of the results of genetic association studies. To overcome this problem the idea of using a gene‐based analysis in which all common variation within a candidate gene is considered jointly has been suggested. In this paper we investigate to what extent the use of gene‐based analyses resolves the non‐replication problem.MethodWe performed gene‐level and meta‐analysis association studies for two cohorts: Cardiovascular Heart Study (CHS) and Framingham (FRAM) using Alzheimer’s disease as a primary outcome. To support our findings, we also performed meta‐analysis following gene‐enrichment study for both cohorts. Analysis was performed separately for males and females and for both sexes. Additional covariates were age, smoking. Gene‐level analysis was performed with fastBAT and enrichment analysis with ClusterProfiler on KEGG database.ResultOur analysis identified a list of highly significant genes, such as TOMM40, APOC1 (all with FDR‐adjusted p‐value < 0.05) and pathways, such as Cholesterol metabolism, Fluid shear stress and atherosclerosis, Proteoglycans in cancer, Lipid and atherosclerosis showed statistically significant associations (FDR‐adjusted p‐value < 0.05) in both datasets and sexes.Meta‐analysis revealed TOMM40 (p‐value = 2.35E‐16), APOC1 (p‐value 4.46E‐13), ENSG00000259648 (p‐value = 8.88E‐06), PEX7 (p‐value = 4.40E‐05), ENSG00000287274 (p‐value = 5.38E‐05) genes for men and women combined; men exclusively revealed ENSG00000259648, TOMM40, and APOC1 (p‐value<1.75E‐05) and women TOMM40 and APOC1 (p‐value<6E‐08).Gene‐enrichment meta‐analysis revealed NOD‐like receptor signaling pathway (adjusted p‐value 3.23E‐07), Lipid and atherosclerosis (p‐value = 5.93E‐05), Yersinia (p‐value = 1.17E‐04) for men and women combined; for men only the pathways are Lipid and atherosclerosis (p‐value = 3.61E‐03), TGF‐beta signaling pathway (p‐value = 3.61E‐03), AGE‐RAGE signaling pathway in diabetic complications (p‐value = 5.18E‐03); and for women Cholesterol metabolism (p‐value = 3.49E‐07), Fatty acid degradation (p‐value = 1.04E‐06), PPAR signaling pathway (p‐value = 1.23E‐05).ConclusionIn this work we were able to identify statistically significant genes and pathways showed replication across the studies and are potentially useful for uncovering genetic mechanisms of AD. However, other things such as genetic heterogeneity may influence disease developing and needed further exploration.

Abstract 6344: HLA and non-HLA associations with childhood and adolescent Hodgkin lymphoma risk

Abstract The genetic etiology for Hodgkin lymphoma (HL) has been investigated with findings reported in both human leukocyte antigens (HLA) and non-HLA genomic regions. However, results of genetic association studies that focus on HL developed among children and adolescent individuals are limited. Given the historically high survival rate, it is reasonable to leverage available genetic data for survivors of childhood/adolescent HL for this investigation. Utilizing existing data from the St. Jude Lifetime Cohort, the Childhood Cancer Survivor Study (CCSS) original cohort and CCSS expansion cohort, we performed a fixed-effects meta-analysis of three genome-wide association studies for a total of 1,286 HL cases, 6,824 other childhood cancer cases and 373 non-cancer controls, all of whom are of European ancestry. Three independent SNPs in the HLA locus (rs28383311, Odds Ratio [OR] = 1.80, P = 2.14×10-21; rs3129198, OR = 1.52, P = 2.05×10-14; rs3129890, OR = 1.51, P = 6.21×10-13) were identified using step-wise conditional logistic regression. HLA SNP rs28383311 had a moderate correlation (r2 = 0.46) with rs2858870 reported previously by Cozen et al. (Blood, 2012) in the HLA-DRA gene region in adolescent/young adults onset HL. HLA SNP rs3129198 had a perfect correlation (r2 = 1.0) with rs2281389 (HLA-DPB1) reported previously by Moutsianas et al. (Blood, 2011) in mostly adults-onset HL. In contrast, SNP rs3129890 had a low correlation (r2 = 0.15) with rs2395185 (HLA-DRA) reported previously by Urayama et al. (JNCI, 2012) in HL cases diagnosed across a wide age range between 16 and 80 years old. Our analysis also identified additional SNPs for non-HLA loci at genome-wide significance level including: 1) rs1432297 (OR = 1.30, P = 2.5×10-8), which is in moderate correlation (r2=0.52) with previously reported rs1432295 (REL); 2) rs13279159 (OR = 1.32, P = 1.7×10-8), which is in high correlation (r2=0.75) with previously reported rs2019960 (PVT1); and 3) rs3824662 (OR = 1.52, P = 3.9×10-10), which had a high correlation (r2 = 0.91) with previously reported rs3781093 (GATA3). In addition, a novel uncommon SNP with a large effect size (rs117361561, OR = 1.95, P = 2.50×10-8, minor allele frequency = 0.02) was identified and mapped to PDGFD, a plausible gene for HL susceptibility. Twelve out 18 (67%) previously reported genome-wide significant non-HLA SNPs were replicated with P < 0.05 based on our meta-analysis. By analyzing early onset HL within pediatric and adolescent age range, we further dissected the associations in HLA locus by replicating three independent SNPs. We also found a novel non-HLA locus and replicated the majority of previous findings in the non-HLA region, suggesting mostly overlapping as well as potentially unique genetic etiology for HL risk across different ages of onset. Citation Format: Cheng Chen, Nan Song, Xiaojun Sun, Qian Dong, Zhenghong Li, Hui Wang, Smita Bhatia, Heather Mulder, John Easton, Jinghui Zhang, Yutaka Yasui, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Leslie L. Robison, Zhaoming Wang. HLA and non-HLA associations with childhood and adolescent Hodgkin lymphoma risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6344.

The genetic susceptibility profile of type 2 diabetes and reflection of its possible role related to reproductive dysfunctions in the southern Indian population of Hyderabad

BackgroundThe genetic association studies of type 2 diabetes mellitus (T2DM) hitherto undertaken among the Indian populations are grossly inadequate representation of the ethnic and geographic heterogeneity of the country. In view of this and due to the inconsistent nature of the results of genetic association studies, it would be prudent to undertake large scale studies in different regions of India considering wide spectrum of variants from the relevant pathophysiological pathways. Given the reproductive dysfunctions associated with T2DM, it would be also interesting to explore if some of the reproductive pathway genes are associated with T2DM. The present study is an attempt to examine these aspects in the southern Indian population of Hyderabad.MethodsA prioritized panel of 92 SNPs from a large number of metabolic and reproductive pathway genes was genotyped on 500 cases and 500 controls, matched for ethnicity, age and BMI, using AGENA MassARRAYiPLEX™ platform.ResultsThe allelic association results suggested 14 SNPs to be significantly associated with T2DM at P ≤ 0.05 and seven of those—rs2241766-G (ADIPOQ), rs6494730-T (FEM1B), rs1799817-A and rs2059806-T (INSR), rs11745088-C (FST), rs9939609-A and rs9940128-A (FTO)—remained highly significant even after correction for multiple testing. A great majority of the significant SNPs were risk in nature. The ROC analysis of the risk scores of the significant SNPs yielded an area under curve of 0.787, suggesting substantial power of our study to confer these genetic variants as predictors of risk for T2DM.ConclusionsThe associated SNPs of this study are known to be specifically related to insulin signaling, fatty acid metabolism and reproductive pathway genes and possibly suggesting the role of overlapping phenotypic features of insulin resistance, obesity and reproductive dysfunctions inherent in the development of diabetes. Large scale studies involving gender specific approach may be required in order to identify the precise nature of population and gender specific risk profiles for different populations, which might be somewhat distinct.

The Genetic Basis of Thyroid Function: Novel Findings and New Approaches.

Genetic factors are major determinants of thyroid function. Over the last two decades, multiple genetic variants have been associated with variations in normal range thyroid function tests. Most recently, a large-scale genome-wide association study (GWAS) doubled the number of known variants associated with normal range thyrotropin (TSH) and free thyroxine (FT4) levels. This review summarizes the results of genetic association studies on normal range thyroid function and explores how these genetic variants can be used in future studies to improve our understanding of thyroid hormone regulation and disease. Serum TSH and FT4 levels are determined by multiple genetic variants on virtually all levels of the hypothalamus-pituitary-thyroid (HPT) axis. Functional follow-up studies on top of GWAS hits has the potential to discover new key players in thyroid hormone regulation, as exemplified by the identification of the thyroid hormone transporter SLC17A4 and the metabolizing enzyme AADAT. Translational studies may use these genetic variants to investigate causal associations between thyroid function and various outcomes in Mendelian Randomization (MR) studies, to identify individuals with an increased risk of thyroid dysfunction, and to predict the individual HPT axis setpoint. Recent genetic studies have greatly improved our understanding of the genetic basis of thyroid function, and have revealed novel pathways involved in its regulation. In addition, these findings have paved the way for various lines of research that can improve our understanding of thyroid hormone regulation and thyroid diseases, as well as the potential use of these markers in future clinical practice.

CTLA-4 polymorphisms and predisposition to digestive system malignancies: a meta-analysis of 31 published studies

BackgroundThe results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies.MethodsThe authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis.ResultsThe pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients with liver cancer and controls, and for rs733618 polymorphism among patients with colorectal cancer and controls in pooled meta-analyses.ConclusionsThis meta-analysis suggested that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer.

A Genome-Wide Association Study of Sprint Performance in Elite Youth Football Players

Pickering, C, Suraci, B, Semenova, EA, Boulygina, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Leońska-Duniec, A, Pająk, B, Chycki, J, Moska, W, Lulińska-Kuklik, E, Dornowski, M, Maszczyk, A, Bradley, B, Kana-ah, A, Cięszczyk, P, Generozov, EV, and Ahmetov, II. A genome-wide association study of sprint performance in elite youth football players. J Strength Cond Res 33(9): 2344-2351, 2019-Sprint speed is an important component of football performance, with teams often placing a high value on sprint and acceleration ability. The aim of this study was to undertake the first genome-wide association study to identify genetic variants associated with sprint test performance in elite youth football players and to further validate the obtained results in additional studies. Using micro-array data (600 K-1.14 M single nucleotide polymorphisms [SNPs]) of 1,206 subjects, we identified 12 SNPs with suggestive significance after passing replication criteria. The polymorphism rs55743914 located in the PTPRK gene was found as the most significant for 5-m sprint test (p = 7.7 × 10). Seven of the discovered SNPs were also associated with sprint test performance in a cohort of 126 Polish women, and 4 were associated with power athlete status in a cohort of 399 elite Russian athletes. Six SNPs were associated with muscle fiber type in a cohort of 96 Russian subjects. We also examined genotype distributions and possible associations for 16 SNPs previously linked with sprint performance. Four SNPs (AGT rs699, HSD17B14 rs7247312, IGF2 rs680, and IL6 rs1800795) were associated with sprint test performance in this cohort. In addition, the G alleles of 2 SNPs in ADRB2 (rs1042713 & rs1042714) were significantly over-represented in these players compared with British and European controls. These results suggest that there is a genetic influence on sprint test performance in footballers, and identifies some of the genetic variants that help explain this influence.

Comprehensive review and annotation of susceptibility SNPs associated with obesity-related traits.

We aimed to summarize the results of genetic association studies for obesity and provide a comprehensive annotation of all susceptibility single nucleotide polymorphisms (SNPs). A total of 72 studies were summarized, resulting in 90,361 susceptibility SNPs (738 index SNPs and 89,623 linkage disequilibrium SNPs). Over 90% of the susceptibility SNPs are located in non-coding regions, and it is challenging to understand their functional significance. Therefore, we annotated these SNPs by using various functional databases. We identified 24,623 functional SNPs, including 4 nonsense SNPs, 479 missense SNPs, 399 untranslated region SNPs which might affect microRNA binding, 262 promoter and 5,492 enhancer SNPs which might affect transcription factor binding, 7 splicing sites, 76 SNPs which might affect gene methylation levels, 1,839 SNPs under natural selection and 17,351 SNPs which might modify histone binding. Expression quantitative trait loci analyses for functional SNPs identified 98 target genes, including 69 protein coding genes, 27 long non-coding RNAs and 3 processed transcripts. The percentage of protein coding genes that could be correlated with obesity-related pathways directly or through gene-gene interaction is 75.36 (52/69). Our results may serve as an encyclopaedia of obesity susceptibility SNPs and offer guide for functional experiments.

Genetic factors are stressed variably by onset age-based sample selection in psoriasis: A hint from major histocompatibility complex region-based analysis.

Large cohort-based genetic association studies have been established over a decade. However, for certain diseases, different results with respect to the genome-wide association study level have been obtained among studies, even for those conducted within the same ethnic groups. We hypothesized that onset age-based sample variables might have a great impact on the results. In the present study, we divided psoriasis patients into several subgroups according to the onset age bracket. We conducted genetic association analysis in the major histocompatibility complex (MHC) region of each patient subgroup with shared control subjects. We found decreases in the numbers of susceptible variants in each subgroup analysis as the onset age increased in the longitudinal analysis. Meanwhile, the pairwise analysis showed that younger patients exhibited greater numbers of genetic risks in the MHC region compared to elder patients, regardless of whether the cut-off values were defined as 20 or 30years old. Similar results were also found among 11-20-, 21-30- and 31-40-year-old groups. Furthermore, when combining the results of both the stepwise regression analysis and the HLA-C*06:02 conditioning analysis, different variants were found to be independently associated with each psoriasis subgroup. Onset age-based sample variables influence the results of genetic association studies, at least in MHC region-based genetic analysis. We suggest that caution is required when selecting samples for genetic association studies to prevent confounders that might be a result of onset age.

Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures.

This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.

Abstract 2598: Predicting breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers using polygenic risk scores

Abstract Women who carry a pathogenic mutation in the BRCA1 or BRCA2 gene are at high risk of breast (BC) and ovarian cancer (OC). Their clinical management usually includes invasive risk-reducing interventions with substantial side effects. Improved personalized cancer risk estimates may help to identify women at particularly high risk or with high risk of disease at early ages who may benefit from early intervention as well as women at lower risk who may opt to delay surgery or chemoprevention. Genome-wide association studies have identified >100 common genetic variants that are associated with BC or OC risks. Several of these variants are also individually associated with risk of BC or OC for BRCA1 and BRCA2 mutation carriers. However, no study has evaluated the combined effects of all the known common genetic variants on BC or OC risk for BRCA1/2 mutation carriers. We constructed polygenic risk scores (PRS) based on results of genetic association studies conducted in the general population. Each PRS was formed by the sum of the number of risk alleles across the variants weighted by their log-Odds Ratio estimate from population-based studies of BC or OC. We investigated 3 PRS for BC (overall, estrogen receptor (ER) positive, and ER-negative) and one PRS for OC. We used data for 15,252 BRCA1 and 8,211 BRCA2 female carriers. The association of each PRS with BC or OC risk was evaluated using a weighted cohort analysis with time to diagnosis as the outcome and estimated the Hazard Ratios (HR) per standard deviation increase in the PRS. All PRS were significantly associated with cancer risks for BRCA1/2 carriers. The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.29 [1.25-1.33], p = 8×10−64). In BRCA2 carriers, the strongest association was seen for the overall BC PRS (HR = 1.26 [1.21-1.31], p = 3×10−27). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These relative risks translate to large differences in absolute risks for carriers: e.g., the OC risk was 6% by age 80 for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Our findings demonstrate that BC and OC PRS derived from studies in the general population are predictive of cancer risks in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models would improve risk prediction and hence inform decisions on cancer risk management. Citation Format: Karoline Kuchenbaecker, Jacques Simard, Kenneth Offit, Fergus J. Couch, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Consortium of Investigators of Modifiers of BRCA1/2. Predicting breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers using polygenic risk scores. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2598.

0184: Genetic association between single nucleotide polymorphisms in the Paraoxonase 1 (PON1) gene and the risk of myocardial infarction in the Tunisian male population

Coronary artery disease (CAD), the leading cause of death worldwide, is a multifactorial disease arising from the complex interplay of genetic and environmental factors. Paraoxonase 1 (PON1) polymorphisms have been implicated as risk factors for CAD, but the results of genetic association studies on the related phenotype of CAD are inconclusive. The aim of the present study was to investigate the association between the PON1 promoter –108 C>T (rs705381) and the coding region Gln192Arg (Q192R, rs662) and Leu55Met (L55M, rs854560) variants with myocardial infarction (MI) in a sample of the Tunisian population. A total of 382 unrelated MI patients and 380 healthy controls were enrolled in this study. Genotyping was performed by the polymerase chain reaction and restriction fragment length polymorphism method (PCRRFLP). The frequencies of the alleles and genotypes between MI patients and controls were compared by the chi-square test. Genotype distribution and allele frequencies of L55M were similar among the control and MI groups. The PON1-Q192R and –108 C>T genotypes exhibited significant differences in allele and genotype frequencies among the MI and control groups. At PON1-192 locus, there were significant differences between patients and controls (p<0.05), leading to significant odds ratios for RR genotype (OR=1.89, CI: 1.21 – 2.94) and R allele (OR=1.37, CI: 1.11 – 1.69). Binary logistic regression analysis also confirmed that RR genotypes have a higher risk of MI (OR=1.75, CI: 1.03 – 2.98). The T allele of –108C>T polymorphism was found to be a risk marker for MI (OR=1.29, CI: 1.05 – 1.58; p=0.011). The present study showed a significant and independent association between the PON1 Q192R and – 108 C>T polymorphisms and MI in the Tunisian male population.

Phenotypic heterogeneity in study populations may significantly confound the results of genetic association studies on alcohol dependence.

The interpretation of genetic studies on alcohol dependence may be confounded by the co-occurrence of substance dependence, psychiatric disorders and alcohol-related comorbidities, for example, cirrhosis. Significant single-marker and haplotypic associations between polymorphisms in the zinc finger gene, ZNF699, and alcohol dependence were reported in the Irish Affected Sib Pair Study of Alcohol Dependence population, one-third of whom had co-occurring substance dependence while 80% had identified psychiatric comorbidity. The aim of this study was to explore variant ZNF699 associations with alcohol dependence while exercising controls for potential confounders. The study population was comprised of 1449 alcohol-dependent cases and 1283 population controls; all were of British or Irish ancestry. None of the cases had a history of dependence on other substances, and the frequency of comorbid depression was low. A separate, ancestry-matched cohort of 196 opioid-dependent cases was also included. Genotyping for the four previously identified SNPs of interest in ZNF699 was performed using K-Biosciences Competitive Allele Specific PCR. No single-marker associations were found between polymorphisms in ZNF699 and alcohol dependence per se. A significant allelic association was found between rs7254880 in ZNF699 and alcohol-related cirrhosis (n=292), using cases with no biopsy evidence of liver disease (n=314) as controls (P=0.013). Significant allelic associations were also found between rs12460279 (P=0.028), rs7252865 (P=0.012) and rs10854142 (P=0.016) in ZNF699 and opioid dependence. Phenotypic variation in study populations may contribute towards the nonreplication of genetic association studies on alcohol dependence; controls for recognised confounding variables should be exercised whenever possible.

BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder

BackgroundAnxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. MethodsWe genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. ResultsVal66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. LimitationsFirst, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. ConclusionsOur findings support the hypothesis that BDNF is involved in the pathophysiology of mental disorders, not only OCD but also GAD. OCD and GAD patients both show lower BDNF plasma levels compared to healthy controls. The BDNF plasma levels are not associated with Val66Met variation.

Genetic aspects of erectile dysfunction

Erectile dysfunction (ED) is a common disorder in man that influences the quality of life of the patient and his partner. Known risk factors for ED comprise diabetes, coronary artery disease, hypertension but also lifestyle modifications such as smoking, diminished physical activity as well as obesity. In this manuscript the current scientific literature about genetics and erectile dysfunction is reviewed. A literature search using the databank PubMed covering the topics genetics and erectile dysfunction was performed and relevant papers selected for presentation. Several aspects of genetics and ED are described in the current literature. Association studies of candidate polymorphisms and ED risk in comparison to healthy controls is a major area of research. Another topic is the genome-wide search for candidate polymorphisms with erectile dysfunction. The paper closes with the presentation of the pharmacogenomic analysis of treatment response to phosphodiesterase-5 inhibitors. The heterogeneous results of genetic association studies are possibly due to small sample sizes of the study population and/or due to ethnic differences of the analyzed populations. This underlines the need for validation of this data in larger prospective multinational multicenter studies.

Genetics of psoriasis.

Psoriasis is a common and debilitating immune-mediated skin disease with a complex genetic basis. Genetic studies have provided critical insights into the pathogenesis of disease. This article focuses on the results of genetic association studies, which provide evidence that psoriasis susceptibility genes are involved in innate and adaptive immunity and skin barrier functions. The potential for disease stratification and the development of more effective treatments with fewer side effects using genetic data are highlighted.

The ontology of genetic susceptibility factors (OGSF) and its application in modeling genetic susceptibility to vaccine adverse events.

BackgroundDue to human variations in genetic susceptibility, vaccination often triggers adverse events in a small population of vaccinees. Based on our previous work on ontological modeling of genetic susceptibility to disease, we developed an Ontology of Genetic Susceptibility Factors (OGSF), a biomedical ontology in the domain of genetic susceptibility and genetic susceptibility factors. The OGSF framework was then applied in the area of vaccine adverse events (VAEs).ResultsOGSF aligns with the Basic Formal Ontology (BFO). OGSF defines ‘genetic susceptibility’ as a subclass of BFO:disposition and has a material basis ‘genetic susceptibility factor’. The ‘genetic susceptibility to pathological bodily process’ is a subclasses of ‘genetic susceptibility’. A VAE is a type of pathological bodily process. OGSF represents different types of genetic susceptibility factors including various susceptibility alleles (e.g., SNP and gene). A general OGSF design pattern was developed to represent genetic susceptibility to VAE and associated genetic susceptibility factors using experimental results in genetic association studies. To test and validate the design pattern, two case studies were populated in OGSF. In the first case study, human gene allele DBR*15:01 is susceptible to influenza vaccine Pandemrix-induced Multiple Sclerosis. The second case study reports genetic susceptibility polymorphisms associated with systemic smallpox VAEs. After the data of the Case Study 2 were represented using OGSF-based axioms, SPARQL was successfully developed to retrieve the susceptibility factors stored in the populated OGSF. A network of data from the Case Study 2 was constructed by using ontology terms and individuals as nodes and ontology relations as edges. Different social network analys is (SNA) methods were then applied to verify core OGSF terms. Interestingly, a SNA hub analysis verified all susceptibility alleles of SNPs and a SNA closeness analysis verified the susceptibility genes in Case Study 2. These results validated the proper OGSF structure identified different ontology aspects with SNA methods.ConclusionsOGSF provides a verified and robust framework for representing various genetic susceptibility types and genetic susceptibility factors annotated from experimental VAE genetic association studies. The RDF/OWL formulated ontology data can be queried using SPARQL and analyzed using centrality-based network analysis methods.

Why It Is Hard to Find Genes Associated With Social Science Traits: Theoretical and Empirical Considerations

We explain why traits of interest to behavioral scientists may have a genetic architecture featuring hundreds or thousands of loci with tiny individual effects rather than a few with large effects and why such an architecture makes it difficult to find robust associations between traits and genes. We conducted a genome-wide association study at 2 sites, Harvard University and Union College, measuring more than 100 physical and behavioral traits with a sample size typical of candidate gene studies. We evaluated predictions that alleles with large effect sizes would be rare and most traits of interest to social science are likely characterized by a lack of strong directional selection. We also carried out a theoretical analysis of the genetic architecture of traits based on R.A. Fisher's geometric model of natural selection and empirical analyses of the effects of selection bias and phenotype measurement stability on the results of genetic association studies. Although we replicated several known genetic associations with physical traits, we found only 2 associations with behavioral traits that met the nominal genome-wide significance threshold, indicating that physical and behavioral traits are mainly affected by numerous genes with small effects. The challenge for social science genomics is the likelihood that genes are connected to behavioral variation by lengthy, nonlinear, interactive causal chains, and unraveling these chains requires allying with personal genomics to take advantage of the potential for large sample sizes as well as continuing with traditional epidemiological studies.

Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma

Chromosomal region 17q12-q21 is one of the best-replicated genome-wide association study (GWAS) hits and associated with childhood-onset asthma. However, the mechanism by which the genetic association is restricted to childhood-onset disease is unclear. During childhood, more boys than girls develop asthma. Therefore, we tested the hypothesis that the 17q12-q21 genetic association was sex-specific. Indeed, a TDT test showed that in the Saguenay-Lac-Saint-Jean familial collection, the 17q12-q21 association was significant among male, but not among female asthmatic subjects. We next hypothesized that the bias in the genetic association resulted from sex-specific and/or age-dependent DNA methylation at regulatory regions and determined the methylation profiles of five 17q12-q21 gene promoters using the bisulfite sequencing methylation assay. We identified a single regulatory region within the zona pellucida binding protein 2 (ZPBP2) gene, which showed statistically significant differences between males and females with respect to DNA methylation. DNA methylation also varied with age and was higher in adult males compared to boys. We have recently identified two functionally important polymorphisms, both within the ZPBP2 gene that influence expression levels of neighboring genes. Combined with the results of the present work, these data converge pointing to the same 5 kb region within the ZPBP2 gene as a critical region for both gene expression regulation and predisposition to asthma. Our data show that sex- and age-dependent DNA methylation may act as a modifier of genetic effects and influence the results of genetic association studies.

Methodological remarks concerning the recent meta-analysis on CYP1A1 polymorphisms-smoking interaction and hepatocellular carcinoma risk

We read with great interest the recent meta-analysis by Yu et al. [1], which evaluated the association between Cytochrome P-450 1A1 (CYP1A1) polymorphisms, cigarette smoking and hepatocellular carcinoma risk. Nine studies were included in their meta-analysis and their study found that the MspI and Ile–Val polymorphisms of CYP1A1 may play important roles in increasing susceptibility to smoking-related hepatocellular carcinoma (HCC). Nevertheless, close inspection of the studies analyzed by the authors revealed some methodological issues that are worth mentioning and clarifying. Adopting the same search strategy and end-of-search date as Yu et al. [1], we have located one relevant case–control study in CNKI with a total number of 102 HCC cases and 102 controls, which have not been included in the meta-analysis [2]. Moreover, a methodological issue needs to be addressed with respect to the data provided in this meta-analysis by Yu et al. The data reported by Yu et al. for the study of Yuan et al. [3] (about HBV carriers for MspI polymorphism) do not seem to be in line with the data actually provided by Yuan et al. [3]. Yu et al. reported that the m1m1 genotype frequency in cases/controls among HBV carriers was 76/49 and the m2m2 was 75/50 respectively, whereas the m1m1 was 75/50 and m2m2 was 76/49 in Yuan et al.’s study. Also, the data reported by Yu et al. for the study of Silvestri et al. [4] are not consistent with the data provided by Silvestri et al. In the study of Silvestri et al., there were only 91 HCC cases and 99 blood donors as controls; however, Yu et al. reported 95 HCC cases and 103 controls for the Ile–Val polymorphism and 107 HCC cases and 115 controls for MspI polymorphism in CYP1A1 gene. Meanwhile, the genotype frequency in cases/controls for the two polymorphisms loci were incorrect; Yu et al. taken the total number for cases and controls in Silvestri et al’s study as the wild homozygous genotype for cases and controls (Table 1 and Table 2 in Yu et al.’s study). Moreover, we can only obtain the genotype frequency of Ile/Val ?Val/Val and Ile/Ile for the Ile–Val polymorphism, and m1m2 ? m2m2 and m1m1 for MspI polymorphism in the study of Silvestri et al., while the separate genotype frequency of Ile/Ile, Ile/Val, Val/Val for the Ile–Val polymorphism (m1m1, m1m2, m2m2 for MspI polymorphism) were unreported. Therefore, Silvestri et al’s study can only be included in the pooled analysis under dominant genetic model, but not under the other three genetic models. However, Yu et al. did not address this in rtmfthe statistical analysis section in their meta-analysis. Moreover, some other methodological issues seem worth commenting. First, the genotype distribution of MspI polymorphism among control subjects disobeyed the law of Hardy–Weinberg equilibrium (HWE) in two studies [5, 6]. The deviation from HWE presents the probability of genotyping errors, selection bias or other bias [7], and the results of genetic association studies might be spurious if the distribution of genotypes in the control groups were not in HWE [8, 9]. Therefore, the authors should carry out subgroup analysis by HWE in controls. Second, as the authors said in the article, the definitions of cigarette smoking were different for the included studies. It is not very suitable to pool the studies with different definitions of cigarette smoking together. Even if the definitions of cigarette smoking were the same for the 3 included studies, there still was a very high risk of reporting bias for F. Liu B. Li (&) Y.-G. Wei W.-T. Wang Department of liver and Vascular Surgery, West China Hospital of Sichuan University, 37 Guo Xue Road, Chengdu 610041, Sichuan Province, China e-mail: cdlibo688@163.com

Host genomics and HCV treatment response

In 2009, an association between the interleukin-28B (IL28B) polymorphism and treatment outcome for genotype 1 (G1) hepatitis C virus (HCV) infection, as well as spontaneous clearance of HCV, was reported. Since the initial publications, over 100 articles have appeared in the peer-reviewed literature, with many more manuscripts in press and abstracts presented at scientific meetings. Despite the proliferation of data concerning the IL28B polymorphism and HCV infection, there remain many critical unanswered questions about clinical implications and the underlying biological mechanisms. In this review, we discuss the basic principles of genome-wide association study methodologies that are important for interpreting the results of genetic association studies. We then review the current literature concerning the association between IL28B variants and interferon (IFN) treatment response in patients with chronic HCV infection, as well as spontaneous HCV clearance. We consider the relevance of the IL28B polymorphism to non-G1 HCV, as well as the special treatment populations of HIV/HCV co-infection and recurrent HCV post-liver transplantation. We review current knowledge of the biological mechanisms underlying this genetic association, including the link to liver IFN-stimulated gene expression, and identify continuing gaps in our knowledge and key research priorities. Finally, pegylated-IFN and ribavirin is no longer the standard of care for the treatment of G1 HCV, and we conclude by considering the relevance of IL28B polymorphisms in the era of direct-acting antivirals.