Evidence For Genetic Association Research Articles

Association of rare and common genetic variants in MOCOS with inadequate response to allopurinol.

The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response. This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients, whose whole genome was sequenced (n = 563). Good responders had a 4:1 or 5:1 ratio of good (serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day) to poor (SU ≥ 0.36 mmol/l despite allopurinol >300 mg/day) responses over 5-6 timepoints, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n = 303), by plasma oxypurinol >20μmol/l. Using the sequence kernel association test (SKAT) we estimated the combined effect of rare and common variants in urate secretory (ABCC4, ABCC5, ABCG2, SLC17A1, SLC17A3, SLC22A6, SLC22A8) and reuptake genes (SLC2A9, SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1, MOCOS, XDH) on allopurinol response. There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.019), and in MOCOS, encoding molybdenum cofactor sulphurase, with allopurinol response (PSKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.002) and MOCOS (PSKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol. We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.

Causal association of circulating cytokines with the risk of lung cancer: a Mendelian randomization study.

Lung cancer is the deadliest and most prevalent malignancy worldwide. While smoking is an established cause, evidence to identify other causal factors remains lacking. Current research indicates chronic inflammation is involved in tumorigenesis and cancer development, though the specific mechanisms underlying the role of inflammatory cytokines in lung cancer pathogenesis remain unclear. This study implemented Mendelian randomization (MR) analysis to investigate the causal effects of circulating cytokines on lung cancer development. We performed a two-sample MR analysis in Europeans utilizing publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms significantly associated with cytokine were selected as genetic instrumental variables. Genetically predicted levels of the chemokine interleukin-18 (IL-18) (OR = 0.942, 95% CI: 0.897-0.990, P = 0.018) exerted significant negative causal effects on overall lung cancer risk in this analysis. Examining specific histologic subtypes revealed further evidence of genetic associations. Stem cell factor (SCF) (OR = 1.150, 95% CI: 1.021-1.296, P = 0.021) and interleukin-1beta (IL-1β) (OR = 1.152, 95% CI: 1.003-1.325, P = 0.046) were positively associated with lung adenocarcinoma risk, though no inflammatory factors showed causal links to squamous cell lung cancer risk. Stratified by smoking status, interferon gamma-induced protein 10 (IP-10) (OR = 0.861, 95% CI: 0.781-0.950, P = 0.003) was inversely associated while IL-1β (OR = 1.190, 95% CI: 1.023-1.384, P = 0.024) was positively associated with lung cancer risk in ever smokers. Among never smokers, a positive association was observed between lung cancer risk and SCF (OR = 1.474, 95% CI: 1.105-1.964, P = 0.008). Importantly, these causal inferences remained robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode and simple mode regressions. Sensitivity analyses also excluded potential bias stemming from pleiotropy. This MR study found preliminary evidence that genetically predicted levels of four inflammatory cytokines-SCF, IL-1β, IL-18, and IP-10-may causally influence lung cancer risk in an overall and subtype-specific manner, as well as stratified by smoking status. Identifying these cytokine pathways that may promote lung carcinogenesis represents potential new targets for the prevention, early detection, and treatment of this deadly malignancy.

184 Genetic Parameters for Human-Directed Behavior and Intraspecific Social Aggression Traits in Growing Pigs

Abstract This study aimed to estimate heritabilities and genetic and phenotypic correlations for human-directed behavior and intraspecific social aggression traits in growing pigs, and to explore genetic and phenotypic correlations among them. Pigs (n = 2,314) were mixed into groups of 18 animals at 69 ± 5.2 d of age and skin lesions (SL) were counted 24 h (SL24h) and 5 weeks (SL5WK) post-mixing. Individual behavioral responses to isolation in a weighing crate (CRATE, 1 = pig performing exploratory behavior to 4 = pig performing serious, persistent attempts to escape) or when alone in an arena while a human directly approached them (IHAT) were assessed within 48 h post-mixing. During the IHAT, three separate scores were given for each pig based on the severity (0 = none to 3 = severe reaction) of their movement, vocalizations, and vigilance. Additionally, pigs were tested for behavioral responses to the presence of a single human observer walking in their home pen in a circular motion (WTP) within 1 and 4 weeks post-mixing recording pigs that followed, nosed or bit the observer. An animal model was used to estimate genetic parameters for all studied traits using the DMU software. Heritabilities (h2) for SL, CRATE and IHAT responses were low to moderate (0.17 to 0.29), with the greatest h2 estimated for speed of moving away from the approaching observer in the IHAT. Low but significant h2 were estimated for nosing (0.09) and biting (0.11) the observer at 4 weeks post-mixing in the WTP test. Positive high genetic correlations (rg) were observed between CRATE and IHAT responses (0.55 to 0.90), and within SL traits (0.60 to 0.94) while positive low to high rg were estimated within the WTP test (0.24 to 0.59) traits. Positive moderate rg were observed between CRATE and central and posterior SL24h. Genetic correlations between CRATE and IHAT test responses and WTP test traits were low, mostly negative (-0.21 to 0.05) and not significant. Low positive rg (0.06 to 0.24) were observed between SL and the WTP test traits except for the lack of rg between posterior SL24h and pigs biting or following the observer during both tests. Phenotypic correlations between CRATE and IHAT responses and SL or WTP test traits were mostly low and not significant. Under the conditions of this study, h2 estimates for all studied traits suggest they could be suitable as a method of phenotyping aggression and fear and/or boldness in pigs for genetic selection purposes. Additionally, there was evidence of genetic associations between aggression and fear indicators. These findings suggest applying selection pressure to reduce the accumulation of lesions is likely to make pigs more relaxed in a crate environment, but to alter the engagement with humans in other contexts that depends on the location of the lesions under selection.

Association between lztfl1 gene variation and risk infection of COVID-19 in holy Najaf province patients

Coronavirus disease 19 (COVID-19), is acute aspiratory syndrome caused by coronavirus 2 (SARS-CoV-2). Factors such as age, health status (cardiovascular disease, diabetes) and gender are the most important risk factors in terms of their relationship to the host ability to infected with COVID-19. However, the genetic association evidence has been unclear yet in our population. This study, demonstrated genetic predisposition investigation to detect SNPs allele locus 3p21.31at of rs11385942 associations with COVID-19 infection. Statistical analysis and DNA sequences analysis were conducted to the study cases. The results showed male incidences is higher than female number (60 cases- 60% male) corresponding (40 cases40% female). COVID-19 impact significantly on C-reactive protein and the age group 55-65 appeared high level of CRP (130.5 ± 58.93). While, DNA sequence using Sanger sequencing method with further alignments analysis showed the association signal at locus 3p21.31 genes homozygous allele AA/AA frequent exist for the rs11385942 as risk allele in sever patients who have diabetes type 1 or 2 and received oxygen supplementation. However, no heterozygous alleles mutant was detected To conclude, that aged patients and male paralleled the severity of COVID-19.

Abstract 2002: A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group

Abstract Background: Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and are more likely to experience morbidity and mortality from infectious toxicities during treatment compared to those without DS. We sought to characterize genetic risk factors for sepsis among individuals with DS-ALL. Methods: We performed a germline genome-wide association (GWAS) study for sepsis among 264 subjects with DS-ALL treated on Children’s Oncology Group (COG) protocols AALL0932 (N=181) and AALL1131 (N=83), for newly-diagnosed standard risk and high risk B-ALL, respectively. Sepsis was defined using Common Terminology Criteria for Adverse Events (v4.0), with a microbiologically confirmed grade 4 or 5 sepsis event reported during any phase of treatment to define the case and comparison groups. Germline genotyping on the Affymetrix SNP 6.0 or Illumina Omni 2.5Exome arrays was imputed to the Haplotype Reference Consortium panel and filtered for quality control. Logistic regression models were used to compare individuals with DS-ALL who experienced sepsis to those who never developed sepsis during treatment. Models were adjusted for principal components of population structure and COG protocol. Analyses included autosomal variants with a minor allele frequency &amp;gt;1% and excluded chromosome 21. Results: We identified 29 individuals (10.9%) with DS-ALL who developed one or more sepsis events during treatment. In genome-wide analyses, we observed 52 variants in eight genomic loci associated with sepsis at P&amp;lt;10-5 among individuals with DS-ALL. Our top signal was rs77917748 (P=6.02x10-7), an intronic variant in a regulatory region of TMEM163, a protein that is essential for zinc homeostasis. Additionally, we identified a strong linkage signal at rs56288508 on chr6p21.2 (P=5.29x10-6). According to data from the Genotype-Tissue Expression (GTEx) project, this locus is associated with whole blood expression of ZFAND3, a zinc finger protein and transcriptional regulator. Additionally, this variant is associated with intestinal infections (P=0.012) in the UK Biobank. Finally, a third variant we identified in our GWAS is on chr6q24.2 (P=4.33x10-6) and shows strong linkage in GTEx with peripheral blood mononuclear cell expression of APOBEC3A, a viral deaminase that lacks zinc binding activity. Notably, this variant is associated with respiratory failure (P=0.0099) in the UK Biobank. Conclusion: We identified evidence of genetic associations for sepsis risk in DS-ALL. These findings suggest zinc homeostasis may be an important factor mediating risk of sepsis during treatment of individuals with DS-ALL. Confirmatory studies and validation in additional cohorts are ongoing. Citation Format: Melissa A. Richard, Meenakshi Devidas, Wenjian Yang, John P. Woodhouse, Vilmarie Rodriguez, Johann K. Hitzler, Reuven J. Schore, Anne L. Angiolillo, Michael J. Burke, Wanda L. Salzer, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Jun J. Yang, Philip J. Lupo, Karen R. Rabin. A genome-wide association study identifies novel sepsis risk loci in children with Down syndrome-associated acute lymphoblastic leukemia: A report from the Children’s Oncology Group [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 2002.

Do leaf nitrogen resorption dynamics align with the slow‐fast continuum? A test at the intraspecific level

Abstract The links between internal nitrogen recycling through the process of resorption from senescing leaves, whole‐plant resource‐use strategies and performance remain elusive. Indeed, tests of such potential linkages are hampered by the classical evaluation of plant nitrogen resorption efficiency (REN) based on ‘snapshots’ of leaf nitrogen concentration from adult and senescent leaves. We significantly increased the resolution for measuring leaf nitrogen resorption by non‐destructively tracking time courses of nitrogen concentration in leaves of 137 natural Arabidopsis thaliana genotypes native to a wide range of climates across Europe, grown in a greenhouse. In addition to the classical measurement of resorption efficiency, we computed the relative maximum resorption rate of nitrogen (RRN), that is, the amount of nitrogen remobilized by a leaf per unit time and per unit nitrogen, together with slow–fast syndrome traits at the leaf and whole‐plant levels. Across genotypes, high rates and efficiencies of nitrogen resorption were associated with low specific leaf area and late flowering. The RRN showed significant heritability, genetic associations and was negatively correlated with the mean annual temperature of the native populations. By contrast, despite the evidence of a correlation with temperature, REN showed lower heritability and no evidence of genetic association, questioning the mechanisms of nitrogen resorption. Overall, our results suggest a much stronger adaptive role for leaf nitrogen resorption than previously uncovered. Read the free Plain Language Summary for this article on the Journal blog.

The effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China

Accumulating evidence has shown that both MDM2 and GNRH2 might be related to Osteosarcoma (OS) susceptibility. The study aimed to evaluate the effects of common variants in MDM2 and GNRH2 genes on the risk and survival of osteosarcoma in Han populations from Northwest China. In the study, we recruited 2292 subjects including 596 OS patients and 1696 healthy controls and genotyped 16 selected tag SNPs (6 from GNRH2 and 10 from MDM2). Genetic association analyses were performed at the genotypic and allelic levels. Survival curves were made for OS patients with different genotypes. Two SNPs, rs1690916 (MDM2, P = 0.0002) and rs3761243 (GNRH2, P = 0.0004), were identified to be significantly associated with OS risk. Moreover, SNP rs3761243 was strongly associated with pathological fracture (P = 2.61 × 10–14), metastasis (P < 2.2 × 10–16), and Enneking stage (P < 2.2 × 10–16) in the OS group. Furthermore, survival curves based on different genotypes of SNP rs3761243 were found to be significantly different (P = 0.0003), suggesting increased risk with more copies of C alleles. Our results provide supportive evidence for genetic associations of MDM2 and GNRH2 genes with susceptibility to OS, and for the positive correlation of SNP rs3761243 in GNRH2 with the survival status of OS patients in Han populations from Northwest China.

Childhood Alopecia Areata: An Overview of Treatment and Recent Patents.

Alopecia Areata (AA) is a systemic autoimmune condition that usually starts in childhood. This article aims to review genetics, therapy, prognosis, and recent patents for AA. We used clinical queries and keywords "alopecia areata" AND "childhood" as a search engine. Patents were searched using the key term "alopecia areata" in Patents.google.com and freepatentsonline. com. Due to an immune-mediated damage to the hair follicles, hair is lost from the scalp and other areas of the body temporarily or even permanently. Children with AA are generally healthy. Evidence of genetic association and increased predisposition for AA was found by studying families with affected members. Pathophysiologically, T- lymphocytes attack hair follicles and cause inflammation and destruction of the hair follicles and hair loss. In mild cases, there would be well-demarcated round patchy scalp hair loss. The pathognomonic "exclamation mark hairs" may be seen at the lesion periphery. In more severe cases, the hair loss may affect the whole scalp and even the whole body. The clinical course is also variable, which may range from transient episodes of recurrent patchy hair loss to an indolent gradually deteriorating severe hair loss. The treatment of AA depends on factors including patients' age, the extent of the hair loss, duration of disease, psychological impact, availability and side effect profile of the treatments. For localized patchy alopecia, topical application of corticosteroids and/or intralesional corticosteroids are the treatment of choice. Other topical treatments include minoxidil, anthralin, coal tar and immunotherapy. In severe resistant cases, systemic immunosuppressants may be considered. Although herbal medicine, acupuncture, complementary and alternative medicine may be tried on children in some Asian communities, the evidence to support these practices is lacking. To date, only a few recent patents exist in topical treatments, including Il-31, laser and herbal medications. Clinical efficacy is pending for these treatment modalities. None of the established therapeutic options are curative. However, newer treatment modalities, including excimer laser, interleukin-31 antibodies and biologics, are evolving so that there may be significant advances in treatment in the near future. AA can be psychosocially devastating. It is important to assess the quality of life, degree of anxiety, social phobia and mood of the patients and their families. Psychological support is imperative for those who are adversely affected psychosocially.

Bone morphogenetic protein 9, and its genetic variants contribute to susceptibility of idiopathic pulmonary arterial hypertension.

Considering the predominant role of rare variants of the Bone morphogenetic protein 9 (BMP9) gene in the occurrence of idiopathic pulmonary arterial hypertension (IPAH), here we conducted a case-control study, together with functional validation, to explore the relationships between variants of the BMP9 gene and development of IPAH. We found minor alleles of rs3740297 (OR: 0.72, 95% CI: 0.59-0.87, P=7.77×10-5) and rs7923671 (OR: 0.76, 95% CI: 0.62-0.93, P=0.009) were significantly associated with decreased risk of IPAH. Minor alleles of rs3740297 and rs7923671 were significantly associated with increased plasma level of BMP9 in both IPAH cases and controls (P<0.001). An allele of rs7923671 showed higher relative luciferase activity compared to that containing G allele (P<0.001). Mechanism exploration found that pulmonary artery smooth muscle cells (PASMC) cell line transfected with rs3740297 C allele construct, miR-149 mimic, and antagomir miR-149 showed more sensitive change of the relative luciferase activity and BMP9 expression. This means minor allele T of rs3740297 could significantly decrease susceptibility of IPAH in Chinese population, possibly by increasing BMP9 expression through losing a miR-149 binding site. Our study provides evidence for genetic associations between two specific variants in the BMP9 gene and plasma level of BMP9, occurrence of IPAH.

Tail colour signals performance in blue tit nestlings.

Indirect sexual selection arises when reproductive individuals choose their mates based on heritable ornaments that are genetically correlated to fitness. Evidence for genetic associations between ornamental colouration and fitness remains scarce. In this study, we investigate the quantitative genetic relationship between different aspects of tail structural colouration (brightness, hue and UV chroma) and performance (cell-mediated immunity, body mass and wing length) in blue tit (Cyanistes caeruleus) nestlings. In line with previous studies, we find low heritability for structural colouration and moderate heritability for performance measures. Multivariate animal models show positive genetic correlations between the three measures of performance, indicating quantitative genetic variation for overall performance, and tail brightness and UV chroma, two genetically independent colour measures, are genetically correlated with performance (positively and negatively, respectively). Our results suggest that mate choice based on independent aspects of tail colouration can have fitness payoffs in blue tits and provide support for the indirect benefits hypothesis. However, low heritability of tail structural colouration implies that indirect sexual selection on mate choice for this ornament will be a weak evolutionary force.

SU84 - THE GLUTAMATE RECEPTOR - GRM3 GENE AND ANTIPSYCHOTIC RESPONSE IN SCHIZOPHRENIA

Background Schizophrenia (SCZ) is a chronic, debilitating mental disorder characterized by positive, negative and cognitive symptoms. Currently, Antipsychotics (AP) are the best treatment for SCZ, but the clinical responses are highly variable across individuals. Many hypotheses have been proposed to explain the inter-individual difference in AP response. The glutamate system is a target for studying the pharmacogenetics of AP based on the research drug pomaglumetad (GRM2/3) that showed similar efficacy to olanzapine in clinical trials, as well as some evidence of genetic association from previous studies. Also, Bitopertin, a glycine reuptake inhibitor also showed promise in alleviating negative symptoms in SCZ. Glycine acts as co-agonist for the NMDA receptor thus influencing glutamate signaling in the brain. The glutamate genes that have been investigated for their roles in predicting AP response in SCZ include GRIN2A, GRM3 and GRIA1. We conducted an association study between variants in the GRM3 gene and AP using the CATIE sample (n=306). 23 SNPs were extracted from the sample. Methods We investigated 23 SNPs across the GRM3 gene using the CATIE sample. We selected 306 European ancestry patients that have been treated with one of 4 AP (olanzapine, risperidone, quetiapine, and ziprasidone). Treatment response was evaluated using the Positive and Negative Syndrome scale (PANSS). All SNPs with the GRM3 gene were selected from the UCSC genome browser (GRCh36/hg19) and extracted from the CATIE sample using PLINK 1.9. CATIE investigators arranged the genotyping at Perlegen Science using the Affymetrix 500 K two chip genotyping platform plus a custom 164 K fill-in chip. Linkage disequilibrium and Hardy-Weinberg equilibrium calculations were conducted using HaploView 4.2, and all statistical analyses were performed using IBM SPSS v24. Results Among the 23 SNPs obtained from the CATIE dataset, only rs274621 was significantly associated with AP response (p=0.02) under a recessive model. However, the results did not remain significant after correction for independent tests. Discussion Several association studies have investigated GRM3 polymorphisms versus clinical response to AP and yielded promising results in the past. We found a trend for rs274621 to be associated with AP response. The rs274621 marker is an upstream variant which may be located in the promoter region of GRM3 and may affect the transcription of the gene. Interestingly, rs274621 was also significantly associated with bipolar disorder in the University College London 1 (UCL1) subsample GWAS. Overall, the analyses of the European ancestry subsample of CATIE did not provide significant evidence for a role of GRM3 in AP responses. However, further studies of the glutamate system in AP response are required.

A novel splicing site IRP1 somatic mutation in a patient with pheochromocytoma and JAK2V617F positive polycythemia vera: a case report

BackgroundThe role of the hypoxia signaling pathway in the pathogenesis of pheochromocytoma/paraganglioma (PPGL)-polycythemia syndrome has been elucidated. Novel somatic mutations in hypoxia-inducible factor type 2A (HIF2A) and germline mutations in prolyl hydroxylase type 1 and type 2 (PHD1 and PHD2) have been identified to cause upregulation of the hypoxia signaling pathway and its target genes including erythropoietin (EPO) and its receptor (EPOR). However, in a minority of patients presenting with this syndrome, the genetics and molecular pathogenesis remain unexplained. The aim of the present study was to uncover novel genetic causes of PPGL-polycythemia syndrome.Case presentationA female presented with a history of JAK2V617F positive PV, diagnosed in 2007, and right adrenal pheochromocytoma diagnosed and resected in 2011. Her polycythemia symptoms and hematocrit levels continued to worsen from 2007 to 2011, with an increased frequency of phlebotomies. Postoperatively, until early 2013, her hematocrit levels remained normalized. Following this, the hematocrit levels ranged between 46.4 and 48.9% [35–45%]. Tumor tissue from the patient was further tested for mutations in genes related to upregulation of the hypoxia signaling pathway including iron regulatory protein 1 (IRP1), which is a known regulator of HIF-2α mRNA translation. Functional studies were performed to investigate the consequences of these mutations, especially their effect on the HIF signaling pathway and EPO. Indel mutations (c.267-1_267delGGinsTA) were discovered at the exon 3 splicing site of IRP1. Minigene construct and splicing site analysis showed that the mutation led to a new splicing site and a frameshift mutation of IRP1, which caused a truncated protein. Fluorescence in situ hybridization analysis demonstrated heterozygous IRP1 deletions in tumor cells. Immunohistochemistry results confirmed the truncated IRP1 and overexpressed HIF-2α, EPO and EPOR in tumor cells.ConclusionsThis is the first report which provides direct molecular genetic evidence of association between a somatic IRP1 loss-of-function mutation and PHEO and secondary polycythemia. In patients diagnosed with PHEO/PGL and polycythemia with negative genetic testing for mutations in HIF2A, PHD1/2, and VHL, IRP1 should be considered as a candidate gene.

Evidence for genetic association between chromosome 1q loci and predisposition to colorectal neoplasia

Background:A substantial fraction of familial colorectal cancer (CRC) and polyposis heritability remains unexplained. This study aimed to identify predisposing loci in patients with these disorders.Methods:Homozygosity mapping was performed using 222 563 SNPs in 302 index patients with various colorectal neoplasms and 3367 controls. Linkage analysis, exome and whole-genome sequencing were performed in a family affected by microsatellite stable CRCs. Candidate variants were genotyped in 10 554 cases and 21 480 controls. Gene expression was assessed at the mRNA and protein level.Results:Homozygosity mapping revealed a disease-associated region at 1q32.3 which was part of the linkage region 1q32.2–42.2 identified in the CRC family. This includes a region previously associated with risk of CRC. Sequencing identified the p.Asp1432Glu variant in the MIA3 gene (known as TANGO1 or TANGO) and 472 additional rare, shared variants within the linkage region. In both cases and controls the population frequency was 0.02% for this MIA3 variant. The MIA3 mutant allele showed predominant mRNA expression in normal, cancer and precancerous tissues. Furthermore, immunohistochemistry revealed increased expression of MIA3 in adenomatous tissues.Conclusions:Taken together, our two independent strategies associate genetic variations in chromosome 1q loci and predisposition to familial CRC and polyps, which warrants further investigation.

A haplotype at intron 8 of PTPRT gene is associated with resistance to Brucella infection in Argentinian creole goats

Brucellosis is the leading zoonosis on a worldwide scale and constitutes a major public health threat in many regions of the world. Several molecular markers associated with natural resistance to intracellular bacterial infection have been identified. Recently seven single-nucleotide polymorphisms (SNPs) located in the PTPRT gene were associated with resistance to Mycobacterium bovis infection in cattle. Here, we perform a case-control study to test if polymorphisms at PTPRT intron 8 might influence the resistance or susceptibility to Brucella infection in goats. DNA samples from 22 seropositive (cases) and 22 seronegative (controls) for brucellosis, unrelated female creole goats, were included in the present study. Four previously reported polymorphisms (SNP1: rs643551276, SNP2: rs651618967, SNP3: rs662137815 and SNP4: rs657542977) and a new SNP (SNP5: chr13: 691695526) were detected by PCR-DNA sequencing method. Genotypic and allelic frequencies differed significantly between cases and controls at SNPs 1, 2, 4 and 5 (p≤0.001). Indeed, the SNP1 TT, SNP2 TT, SNP4 CC and SNP5 TT genotypes were associated with absence of Brucella-specific antibodies (ORs=0.019 to 0.045). Moreover, haplotype association analysis revealed a significant association of the TTCCT haplotype with protection to Brucella infection (p≤1×10−4; OR=18), including the major allelic variants associated with resistance. These results represent the first evidence of genetic association between polymorphisms in the PTPRT gene and absence of brucellosis in goats.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer Disease, affecting ~ 40% to 60% of individuals with AD (AD with psychosis, AD+P). In comparison to AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate SNPs with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and Alzheimer disease. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy, and calcium channel signaling. These findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

IFITM3 and severe influenza virus infection. No evidence of genetic association.

Influenza virus infection (IVI) is typically subclinical or causes a self-limiting upper respiratory disease. However, in a small subset of patients IVI rapidly progresses to primary viral pneumonia (PVP) with respiratory failure; a minority of patients require intensive care unit admission. Inherited and acquired variability in host immune responses may influence susceptibility and outcome of IVI. However, the molecular basis of such human factors remains largely elusive. It has been proposed that homozygosity for IFITM3 rs12252-C is associated with a population-attributable risk of 5.4 % for severe IVI in Northern Europeans and 54.3 % for severe H1N1pdm infection in Chinese. A total of 148 patients with confirmed IVI were considered for recruitment; 118 Spanish patients (60 of them hospitalized with PVP) and 246 healthy Spanish individuals were finally included in the statistical analysis. PCR-RFLP was used with confirmation by Sanger sequencing. The allele frequency for rs12252-C was found to be 3.5 % among the general Spanish population. We found no rs12252-C homozygous individuals in our control group. The only Spanish patient homozygous for rs12252-C had a neurological disorder (a known risk factor for severe IVI) and mild influenza. Our data do not suggest a role of rs12252-C in the development of severe IVI in our population. These data may be relevant to recognize whether patients homozygous for rs12252-C are at risk of severe influenza, and hence require individualized measures in the case of IVI.

Tu1256 Exploring the Association Between Genetic Polymorphisms and Swallowing Motor Cortex Excitability Induced by Repetitive Transcranial Magnetic Stimulation: Is Response Predicted by Genetic Predisposition?

Introduction Non-invasive brain stimulation such as repetitive Transcranial Magnetic Stimulation (rTMS) is used to manipulate excitability in the swallowing motor cortex. However, the molecular mechanisms controlling this excitability remain unknown. Swallowing neurophysiology and impairments might be in part driven by genes. The aim of this study was to determine whether the variability in excitability after 1 Hz and 5 Hz rTMS within the pharyngeal motor cortex might be affected by putative selected single nucleotide polymorphisms (SNPs). Methods 11 SNPs from 7 genes ( BDNF, COMT, TRKB, APOE, DRD2, GRIN2B and GRIN1 ) were selected a priori to explore possible link between neurophysiological outcomes after rTMS intervention with high (5 Hz) and low (1 Hz) frequencies. A total of 41 healthy young (mean age 25.4 ± 4.6 years) volunteers were investigated. All subjects were assessed for corticobulbar excitability after single-pulse TMS. Repeated measurements of motor evoked potentials (MEPs) from the pharynx were recorded before and for up to one hour after the interventions of 1 Hz and 5 Hz rTMS. Salivary DNA was collected and process post-hoc and SNPs correlated with pharyngeal MEPs and interventions (1 vs. 5 Hz rTMS). Results Non-carriers of the minor G allele from SNP rs6269 from COMT gene are more likely to be non-responders ( P -value =0.026), while those carrying G allele are more likely have inhibitory and excitatory outcomes after delivering 1 Hz and 5 Hz rTMS. Cross-tabulation analysis with chi square indicated there was a significant difference between 5 Hz rTMS outcome and one SNP - DRD2 rs1800497: specifically carriers of minor allele A from this DRD2 gene were more strongly inhibited ( P -value =0.03) while non-carriers were more likely to represent non-responders. Conclusion We now report possible evidence for genetic associations with the neuromuscular control of swallowing influenced by rTMS paradigms. Two SNPs from COMT and DRD2 genes appear to play a role in pharyngeal cortex excitability depending on the stimulation applied. Further research is needed to establish more detailed information which might be used in developing more stratified approach in the field of dysphagia therapy with non-invasive brain stimulation. Disclosure of Interest None Declared

Neurodegenerative Diseases: Phenome to Genome Analysis

Genome-Wide Association Studies (GWAS) tools are an attractive starting point for disease target discovery. Genetic association evidence provides a strong link to disease phenotypes across diverse human DNAs. The National Center for Biotechnology Information (NCBI) Phenome-Genome Integrator tool (PheGenI) was used to identify genes associated with neurodegenerative disease phenotypes (NeuroGenes). Four hundred ninty-nine known proteins and 30 uncharacterized proteins were found to be associated with diverse neurological diseases including Alzeheimer’s, amyotrophic lateral sclerosis (ALS), epilepsy, multiple scelerosis, stroke and Parkinson’s. The NeuroGenes also were associated with other diseases and associated disorders. Using diverse bioinformatics and proteomics tools, an atlas of the NeuroGenes was created to facilitate rational biomarker and drug target discovery. NeuroGenes protein expression was detected in diverse body fluids. The NeuroGenes were categorized into functional classes of proteins using protein motif and domains analysis tools. Expression Quantitative Trait Loci (eQTL) analysis identified single nucleotide polymorphisms (SNPs) associated with mRNA expression across diverse sets of samples from Alzheimer’s disease, Parkinson’s disease, brain infarction, multiple sclerosis, schizophrenia, stroke, mental retardation and neurological cancers. Thirty uncharacterized proteins encompassing structural protein, translation initiation factor, GDP/GTP exchange factor (GEF), transmembrane proteins, tubulin/histonebinding and a lysosomal hydrolase were identified as putative proteins for dementia, Parkinson’s, neurobehavior, multiple scelerosis and ALS. These results may provide new biomarkers for neurological diseases.

Increased risk forCampylobacter jejuniandC. coliinfection of pet origin in dog owners and evidence for genetic association between strains causing infection in humans and their pets

We compared Campylobacter jejuni/coli multilocus sequence types (STs) from pets (dogs/cats) and their owners and investigated risk factors for pet-associated human campylobacteriosis using a combined source-attribution and case-control analysis. In total, 132/687 pet stools were Campylobacter-positive, resulting in 499 strains isolated (320 C. upsaliensis/helveticus, 100 C. jejuni, 33 C. hyointestinalis/fetus, 10 C. lari, 4 C. coli, 32 unidentified). There were 737 human and 104 pet C. jejuni/coli strains assigned to 154 and 49 STs, respectively. Dog, particularly puppy, owners were at increased risk of infection with pet-associated STs. In 2/68 cases vs. 0.134/68 expected by chance, a pet and its owner were infected with an identical ST (ST45, ST658). Although common sources of infection and directionality of transmission between pets and humans were unknown, dog ownership significantly increased the risk for pet-associated human C. jejuni/coli infection and isolation of identical strains in humans and their pets occurred significantly more often than expected.

Genome-wide association study of retinopathy in individuals without diabetes.

BackgroundMild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes.MethodsA working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy.ResultsNo SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension.ConclusionsThis GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.