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ImportanceUnderstanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms.ObjectiveTo identify components of genetic liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component.Design, Setting, and ParticipantsUsing data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with DSM-IV BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022.Main Outcomes and MeasuresPRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale.ResultsOf 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania β = 0.29; 95% CI, 0.23-0.34; P = 3.04 × 10−25; psychosis β = 0.05; 95% CI, 0.04-0.07; P = 2.33 × 10−13) and the components that differentiate each of schizophrenia (mania β = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis β = 0.03; 95% CI, 0.01-0.04; P = 1.0 × 10−4) and BD (mania β = 0.14; 95% CI, 0.09-0.20; P = 1.99 × 10−7; psychosis β = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (β = 0.14; 95% CI, 0.08-0.20; P = 4.32 × 10−6) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (β = 0.01; 95% CI, 0.003-0.03; P = .02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (β = 0.03; 95% CI, 0.01-0.05; P = .005). Depression was associated with higher MDD differentiating component (β = 0.07; 95% CI, 0.01-0.12; P = .01) but lower BD differentiating component (β = −0.11; 95% CI, −0.17 to −0.06; P = 7.06 × 10−5).Conclusions and RelevanceIn this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.

Behcet’s disease (BD) is a complex, multifactorial rare disease, which is poorly understood. Genetic and environmental factors contribute to BD, but the process of diagnosis is challenging with inconsistent clinical manifestations. A recent survey of individuals living with rare disease(s) in Northern Ireland revealed ~50% of individuals receive ≥1 misdiagnosis with 1/20 seeing >10 doctors. Individuals with BD report a range of symptoms, which are variable in onset, severity, and frequency for this systemic vasculitis. Patients describe prolonged journeys to diagnosis with multiple healthcare professionals and medical specialties; there is no BD specialist in Northern Ireland. Using invitations via social media, voluntary groups, and direct contact we are using surveys incorporating micro-narratives, one-to-one semi-structured interviews, and focus groups to collect detailed family histories and stressor information to help characterise recurrent features in patients living with BD and their relatives in Northern Ireland. BD is most often reported in populations along the Silk Road. The highest prevalence is reported in Turkey at 20-420/100,000, compared 1.5/100,000 individuals in the UK. Mapping through general practitioners revealed a much higher than expected prevalence of 12.6/100,000 in the Northern Ireland population. Clusters were observed in Co. Down and Co. Antrim and plotted with social-demographic information. This high ‘UK’ prevalence and the identification of several families with multiple members diagnosed makes NI ideal to explore genetic and epigenetic risk factors for BD. This project involves deep phenotyping and strategies to improve recognition of Behcet’s disease, build collaborative partnerships, improve data collection, enhance training, and information sharing., The National Rare Disease Office (NRDO), initiated in June 2015, collates and disseminates Irish rare disease (RD) information. The prevalent nature of RD (1 in 16 of the population, approximately 80% of which has a genetic basis) and the burden to the health care system is under-recognised and a neglected public health issue. Awareness of rare diseases is a challenge, especially for GPs who each care for > 90 RD patients. The NRDO has made 58 presentations, lectures and publications and received numerous enquiries (58% of contacts from patients/ families, 25% from health care professionals and 4% researchers). Mapping Irish RD clinical and research expertise is developing through Orphanet Ireland. Enrolment of clinical expert centres has increased by 50%,but only, Aims To assess the tumour surveillance advice given to patients in Northern Ireland with confirmed PTEN hamartoma tumour syndrome (HTS). Methods We used the surveillance advice laid out by the Pan Thames Cancer Genetics Group in 2014 to benchmark our patients against. A coding search was carried out on our regional information management system to identify all patients with a confirmed diagnosis. The written/ electronic notes of these patients were reviewed. We adhered to the National PTEN audit inclusion criteria of including patients older than16 years, those with a pathogenic/likely pathogenic PTEN mutation or at 50% risk and those who had received advice between 01/08/10 - 01/08/2015. Results 21 patients were identified. All patients had a pathogenic PTEN mutation. 6 children were excluded. 1 adult was excluded due to lack of documented advice. 6 patients had a cancer diagnosis. 9 patients had a positive family history of cancer. Annual breast screening was recommended for 67% of patients which involved mammography in 83% and MRI in 17%. Annual thyroid USS and TFTs were recommended for 54% and 31% of patients respectively. 16% of female patients had gynaecology referrals completed. An annual dermatological review was recommended for 23% of patients. Widely variable colonoscopy and renal USS screening was recommended for 77% and 65% of patients respectively. No cases of Lhermitte-Duclos disease were identified vs 12% in the national UK audit. Conclusions There is a need for regional PTEN tumour surveillance guidelines to be produced and implemented through a regional PTEN specialist clinic., Catastrophic genomic alterations can drive unusually aggressive cancer phenotypes. We describe a diagnostically challenging rapidly fatal case of medullary thyroid carcinoma (MTC) occurring in a young, morbidly obese man presenting with diffuse bone marrow involvement and disseminated intravascular coagulation. Whole-exome sequencing and shallow whole-genome sequencing was carried out for the primary tumour and multiple metastases. We identified three germline SNP’s within the RET proto-oncogene which remained undetected using routine hospital genetic testing procedures. Indeed, one of the variants identified (L769L) has been previously reported in literature to be associated aggressive MTC presentation, yet remains untested for in the routine diagnosis of MTC. Supported by findings from shallow whole genome sequencing, we report for the first time in thyroid cancer, the occurrence of a catastrophic “chromothripsis-like pattern” (CTLP) event, which involved shattering of chromosome 4 leading to complete abrogation of normal chromosomal function, in addition to dramatic wide-spread copy number aberrations (CNA), across both primary tumour and bone marrow samples. We further describe the presence of loss-of-heterozygosity (LOH) in key genes involved in DNA repair mechanism pathways such as ATM, which possibly facilitated the CTLP event, in addition to LOH in other disease-associated genes such as ALK and NOTCH1 as key drivers of the aggressive and rapidly fatal clinical course in this patient and unresponsiveness to the standard-of-care targeted agent chosen. Given a possible rapid generation of tumor neo-antigens as a result of the CTLP event, immunotherapy may have been more suitable as a treatment option. Moreover, the presence of disease-associated SNP’s within the RET proto-oncogene, support their inclusion as part of routine RET genetic testing for aggressive MTC cases. These results provide a rationale for application of comprehensive genomic analysis of cancers presenting with unusually aggressive behavior to facilitate more appropriate therapeutic options and diagnoses., The Target 5000 research project aims to provide genetic testing for the estimated 5,000 people in Ireland who have an inherited retinal condition. Many clinical trials are available for patients with sight loss, however, many such trials require patients to have their causative mutation identified in order to enter the trial. The objective of the study is to genetically characterise patients with inherited retinal degenerations (IRDs) in Ireland and in principle to make clinical trials more accessible to some Irish people suffering from sight loss. The study also seeks to identify previously undiscovered pathological mutations in a panel of known retinopathy genes evaluated utilizing target capture next generation sequencing (NGS). Thus far in the study, as part of Target 5000 roughly 10% of the Irish IRD population has been sequenced and the results obtained are encouraging. Target 5000 offers not only a chance to discover new causative mutations, but is vital in giving patients access to information regarding the pathogenesis of their disease. Over 50 novel mutations have been discovered, as well as some previously ambiguous phenotypes resolved. More precise matching of genotype with phenotype from this study and similar studies globally should start to enable clinicians to better formulate accurate future diagnoses and at times prognoses., MicroRNAs are understood to play a functional role within the establishment of epigenetic marks and are in turn under epigenetic control. Emerging evidence suggests microRNAs are vital for both kidney development and renal function. This study aimed to identify differential methylation affecting microRNAs in patients with end-stage renal disease (ESRD). Methylation status was determined for 485,577 unique CpG sites in 105 individuals with ESRD and 52 donor controls with no evidence of renal disease using the HumanMethylation450K BeadChip array (Illumina). Statistically significant associations (P, Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease characterized by rapid-onset loss of upper and lower motor neurones, resulting in progressive paralysis and death from respiratory failure. Schizophrenia is a neuropsychiatric disease with positive symptoms, negative symptoms and impairment over a range of cognitive abilities. We have recently shown that schizophrenia occurs more frequently than expected in the pedigrees of ALS patients, suggesting an aetiological relationship between both diseases. Using linkage disequilibrium score regression with summary statistics for GWAS of ALS and schizophrenia comprising over 100,000 unique individuals, we estimated the genetic correlation between ALS and schizophrenia to be 14.3% (95% CI 7.05-21.6; p = 1×10-4). Up to 0.12% of the variance in ALS was explained by schizophrenia polygenic risk scores (p = 8.4×10). We leveraged the apparent pleiotropic relationship between ALS and schizophrenia to identify five potential novel ALS-associated genomic loci at conditional false discovery rate < 0.01. Diagnostic misclassification in the schizophrenia cohort did not contribute significantly to our observations (BUHMBOX p = 0.94) and we estimated that 4.86% (2.47-7.13%) of ALS cases would need to be misdiagnosed as schizophrenia to observe our genetic correlation estimate under a true genetic correlation of 0%. Our results indicate that the lifetime risk for comorbid ALS and schizophrenia increases from 1 in 40,000 to 1 in 34,336, which would require an incident cohort of 16,488 ALS patients to observe epidemiologically. Our findings suggest shared underlying biology between ALS and schizophrenia which will direct novel approaches in research and therapeutic development., Background Imprinted genes are autosomal, but only expressed from one parental allele and are often clustered in small groups. They play an important role in the regulation of normal mammalian development. Differentially methylated regions (DMR) on each allele are important in regulating the genes, with marks being characterised as primary or secondary DMRs, depending on whether they are inherited from the germ cells or arise later, respectively. Imprinting disorders such as Prader-Willi Syndome (PWS) and Beckwith-Weidemann Syndrome (BWS) arise either from uniparental disomy or faulty DNA methylation. We wished to determine 1) which of the loci are most sensitive to loss of methylation 2) to more precisely define the sensitive regions and 3) determine what happens at primary versus secondary imprints. Methods Stable knockdowns of the maintenance methyltransferase DNMT1 were generated in hTERT-immortalised adult fibroblasts using shRNA. Genome wide methylation levels were assayed using the Illumina 450k BeadChip array and analysed using bioinformatic approaches. Results We found that 1) the imprinted loci varied extensively in their sensitivity to loss of methylation 2) the extended locus involved in PWS was particularly sensitive 3) that loss of methylation at primary DMR appears to drive gains in methylation at secondary DMR. Conclusion Our results point to a mechanistic link between primary and secondary DMR which may explain why imprints are difficult to reprogram in somatic tissues., Osteoarthritis (OA) is a degenerative joint disease that affects millions of people globally with no disease-modifying strategies yet available. Our understanding of the pathology of OA is inadequate and this impedes investigation of efficient diagnosis and treatment. To expand our understanding of the underlying cellular pathology of OA, we studied a monogenic condition, familial osteochondritis dissecans (FOCD), associated with a known mutation in the ACAN gene. Patients with FOCD develop early onset OA with multiple joint involvement. The objectives of the project were to investigate the cellular pathogenesis of FOCD by studying (a) chondrogenesis of patient-derived bone marrow-mesenchymal stem cells (BM-MSCs) and (b) induced pluripotent stem cells (iPSCs) generated from patient fibroblasts. Our findings revealed that the mutation resulted in a misfolded or unfolded aggrecan protein, which accumulated in the rough endoplasmic reticulum (rER) during protein production. The consistent accumulation resulted in ER stress throughout chondrogenesis. Moreover, the rER stress caused abnormal or disregulated global extracellular matrix (ECM) production and assembly. Importantly, ECM composition analysis indicated that the patient chondrocytes produced abundant amounts of OA-associated markers. Using patient-specific stem cell models, we have discovered a cellular pathogenesis of FOCD involving abnormal cell function and defective tissue formation, contributing to the OA phenotype., Aims The Irish Travellers are a nomadic population primarily found within Ireland and the UK. Consanguineous unions are common, and as a population they are socially and genetically isolated from the surrounding, “settled” Irish population. Previous low-resolution genetic analyses suggested a common Irish origin between the settled and the Traveller populations. It is not known, however, what is the extent of population structure within the Irish Traveller population, the time of divergence from the general Irish population, and the extent of autozygosity. Methods We recruited Irish Travellers from across Ireland and the UK. For inclusion, a participant had to have had at least three grandparents with a surname associated with the Irish Travellers. DNA was extracted from saliva samples, and genotypes were generated using the Illumina OmniExpress SNP genotyping platform. With this data, we investigated population structure using fineStructure, quantified the levels of autozygosity with PLINK, and estimated a time of divergence using a method based on Identity by Descent (IBD) segment sharing. Results We merged, cleaned, and analysed data from 42 Irish Travellers, 2232 settled Irish, 2039 British, 143 Roma Gypsies, and 931 individuals from 57 world-wide populations. We confirm an Irish origin for the Irish Travellers, demonstrate evidence for population substructure within the population, confirm high levels of autozygosity consistent with a consanguineous population, and for the first time provide estimates for a date of divergence between the Irish Travellers and settled Irish. Conclusion Our findings have implications for disease mapping within Ireland, and they additionally inform on the social history of the Irish Traveller population., Copy number variants at 16p13.11 have been described in association with a variety of neurodevelopmental disorders. While deletions of this region are perhaps better described, the clinical significance of the reciprocal duplication is less clearly defined. Phenotypes reported in association with the duplication include developmental delay, speech delay, behavioural difficulties and neurodevelopmental phenotype such as autism, schizophrenia and ADHD. However, the region appears to be subject to variable expressivity and incomplete penetrance. To date we have detected duplications of 16p13.11 in 5 probands using oligonucleotide array CGH. Of these patients 3 showed duplications within the typical ~1.5Mb duplication region while 2 patients had a larger ~2.8Mb duplication, encompassing all of the above region. The clinical phenotype of these patients will be described. Two of these patients have inherited the duplication from their mothers, one was a de novo finding and the inheritance of the others is currently unknown. One of the maternal duplication carriers are also known to have a phenotype. Our data provides further clinical information on the phenotypic features of patients with this syndrome and provides more evidence for the pathogenic nature of this duplication., Introduction Patients referred to the NI Regional Cancer Genetics Service for genetic counselling were sent a questionnaire to evaluate patient satisfaction. The questionnaire focused on satisfaction surrounding the referral process, waiting times and communication during and after the appointment. Method One hundred patients, whose episode of care was completed between November 2015 and June 2016, were sent an anonymised structured questionnaire by post. Patients were seen by a genetic counsellor for assessment of their family history of cancer, predictive testing and genetic mutation screening Results To date (23/06/2016) the questionnaire response rate is 34%. So far 91% have expressed satisfaction with the service that they received. Useful comments and observations have been feedback in the questionnaire to aid service improvement. Data collection will be completed imminently to allow for complete analysis. Discussion Useful data has been collected which reinforces the service currently being delivered by genetic counsellors whilst also highlighting areas of service development., Leber’s Hereditary Optic Neuropathy (LHON) is one of the most commonly inherited optic neuropathies and results in significant visual morbidity among young adults. 95% of LHON patients will present with one of three primary mitochondrial mutations; G3460A, G11778A and T14484C. We describe a novel real time diagnostic test to detect the three common mutations leading to LHON. The test uses a combination of multiplex allele specific PCR (ARMS PCR) in combination with high resolution melt curve analysis to detect the presence of the G3460A, G11778A and T14484C mutations. PCR primer sets were designed to produce a control PCR product and PCR products only in the presence of the 3460A, 11778A and 14484C mutations in a multiplex single tube format. Products produce discrete well separated melt curves allowing clear detection of the mutations. The test has proved to be robust, cost and time effective with the real time closed tube system taking approximately 1 hour to complete. This test provides a simple, robust, easy to read output that is both cost and time effective, thus providing an alternative method to individual endpoint PCR – RFLP, PCR followed by Sanger / pyrosequencing and next generation sequencing. It will also allow diagnostic laboratories to detect 95% of LHON causing mutations in a single tube assay allowing diagnostic laboratories to avoid costly NGS assays for the vast majority of LHON patients, thus allowing resources to be focussed on patients with unknown mutations requiring further analysis., Atherosclerotic coronary artery disease (CAD) is a progressive chronic inflammatory condition that can lead to Major Adverse Cardiac Events (MACE) such as heart attacks. Currently there is no definitive test to predict MACE risk. Tumour necrosis factor alpha converting enzyme (TACE), also known as A Disintegrin And Metalloproteinase 17 (ADAM17) is a membrane-anchored protein responsible for the ectodomain shedding of a variety of transmembrane proteins such as cytokines, chemokines, growth factors and their receptors. TACE has been linked to several major acute and chronic inflammatory diseases including atherosclerosis. The aim of this study was to investigate if TACE may be a valuable predictive biomarker for CAD and MACE risk. TACE levels were measured in the plasma of CAD patients including those with acute coronary syndrome (ACS) and elective patients attending the catheterisation laboratory for coronary angiogram. TACE levels were measured using ELISA and quantitative real time PCR. Levels were compared with control samples collected from apparently healthy individuals and a subset of patients with no CAD as evidenced by coronary angiogram. Other factors that might affect TACE detection were also measured including sample type and storage time. To date 207 consecutive CAD patients and 40 controls have been recruited to the study. Results demonstrate that CAD patients have higher levels of plasma TACE in comparison to controls. TACE protein levels were especially highest in those ACS and elective patients with a previous history of MACE. Results to date indicate that TACE may be a useful marker to predict disease progression and recurrent MACE in CAD patients., Introduction NRG1 (neuregulin1) is a candidate tumour suppressor gene. NRG1 encodes ligands for members of the ERBB family, and has been shown to be silenced by methylation in breast cancer1. Breast and thyroid cancers share some genetic loci (e.g. PTEN, STK11), and an increased risk of thyroid cancer has been noted in survivors of breast cancer2. A single nucleotide variant (C>G) in NRG1 (rs2439302), has been associated with increased risk of non-medullary thyroid cancer3. Aim Our aim was to investigate the association between rs2439302 in NRG1 and predisposition to thyroid and breast cancers in an Irish population. Methods A two-arm case-control study was undertaken. Patients with mutations in high-risk cancer susceptibility genes were excluded. Controls included adults with no personal or familial history of breast or thyroid cancers. Male controls were included in thyroid case- control analysis only. DNA was extracted from whole blood/buccal swabs by ethanol precipitation. Genotyping was performed using Taqman-based PCR. Results 257 patients with thyroid cancer, 518 with breast cancer and 367 unaffected controls were genotyped. Homozygous carriers of the variant were found to have an increased risk of thyroid cancer (OR1.89 (1.21-2.95), p=0.005), but risk for mono-allelic carriers was not significantly increased (OR1.27 (0.87-1.84), p=0.21). The presence of the variant was not associated significantly with breast malignancy for mono-allelic (OR1.31 (0.95-1.8), p=0.095) or biallelic mutation carriers (OR1.15 (0.76-1.73), p=0.51). Conclusion Homozygous carriers of the G allele were found to be at increased risk of thyroid cancer, but no association was observed between the variant and breast cancer., The UGT1A gene family encode (UGT) activity that facilitate the transfer of glucuronic acid to a range of xenogenous and endogenous substrates, the polar end products of which are better suited for elimination through urine and bile. UGT1A genes exhibit an inducible pattern of expression regulated through the activities of such nuclear receptors (NRs) as pregnane X receptor (PXR) farensoid X receptor (FXR) and liver X receptor (LXR) that form a complex interactive network of ‘sensors’ to facilitate the elimination of potentially harmful metabolites and exogenous toxins. We have previously reported that activation of vitamin D receptor (VDR) through both synthetic agonists and nutritionally derived ligands, can induce the expression of both phase I metabolic (CYP3A) and phase III transporter (ABCA1) genes. Little is known however, as to how activated VDR may impact upon the regulation of phase II genes such as UGT1A1. In this study we demonstrate that ligand-activated VDR can significantly enhance the expression of several members of the UGT1A gene family. With particular respect to UGT1A1, we identify within the proximal promoter region of this gene a functional vitamin D response element (VDRE) also recognized by PXR but distinct from previously established regulatory elements that mediate FXR and LXR signalling. Based upon our data, we propose a model for VDR and circulating levels of vitamin D as maintaining stable expression of phase II and functionally related genes as a means to provide baseline protection against the effects of toxic xeno and endobiotic metabolites., Depression is a complex disorder with multiple symptoms, including a persistent low mood, anhedonia and cognitive impairments, and is currently the third leading cause of global disability. The underlying pathophysiology of depression is poorly understood but a growing body of evidence supports an important role for the microbiome in the aetiology of depression and other psychiatric disorders. While much interest is currently focused on the role of the microbiome-gut-brain axis in brain physiology and neurochemistry, the importance of the oral microbiome has received little attention. The aim of this study is to characterise the oral microbiome in adults with severe depression versus matched controls with no history of the disease. To achieve this, participants were asked to complete an online validated mental health survey and to provide a saliva sample. We identified 46 individuals who met the DSM-V criteria for severe depression and 46 age and sex-matched controls with no history of depression. Bacterial DNA was extracted from the saliva samples and 16S rRNA surveys were conducted using next generation sequencing. Differences in the bacterial community composition of the oral microbiota between patients and controls were determined. Metagenomic analyses were conducted using machine learning and computational intelligence algorithms using the 16S RNA data to generate inferred metagenome feature sets. Charting the oral microbiome in depressed patients could therefore provide new insights into the development of the condition, and lead to the identification of novel diagnostic and therapeutic response biomarkers., The nuclear receptors (NRs) pregnane X receptor (PXR) and constitutive androstane receptor (CAR) modulate transcriptional networks that dictate the bioavailability of many endogenous and exogenous compounds such as steroid hormones and therapeutic drug compounds. Elucidating those factors that invoke PXR/ CAR activity has been important for understanding the genetic basis for both metabolic disease and inter-individual variations in drug response. PXR is most closely related to Vitamin D receptor (VDR) for which there is relatively little is known for how this NR may impact upon these same physiological processes. In this study, we employed enteric cell models and ex-vivo based human colon explants to examine how activated VDR may impact upon the expression of genes of a metabolism and transporter function. We find that in relation to PXR and other evaluated NRs, VDR is the most efficient and dominant receptor for induced expression of CYP2B6, CYP3A4/5 and ABCA1. We note that upon activation with the synthetic agonist EB1089, VDR will achieve striking and sustained elevated expression of CYP3A4 at mRNA, protein and enzymatic level suggesting the potential for selective metabolic gene targeting through ligand design. In addition, we report members of the UGT1A gene family to be novel VDR regulated genes, thus extending the known metabolic effects of vitamin D to also encompass expression of phase II (conjugating) genes. This study intimates that systemic vitamin D status and/or activating VDR ligands may have pharmacokinetic relevance to co-administered drug regimes., Ancient genomes are often typically analysed with regard to ancestry and physical phenotype. Less common is examination and identification of genetic diseases, primarily due to the very low numbers of samples sequenced and poor level of sequencing related to the difficulties in sequencing from ancient DNA. Here we present the results of analysing 21 ancient Irish genomes. The data were screened for a wide range of pathogenic genotypes and markers. Giving information for the potential effects and prevalence of certain conditions as well as the earliest known confirmation of their presence. Using records of the remains, we also examined if any displayed phenotypes correlated to identified diseases., Coronary Artery Disease is the largest contributor of CVD, the leading cause of death worldwide. It is caused by atherosclerosis, a build-up of cholesterol in the blood vessels and chronic inflammation. The NLRP3 inflammasome plays a critical role in the secretion of IL-1β, and there is significant evidence that it is involved in the pathogenesis of a number of inflammatory diseases including atherosclerosis. Recent studies demonstrate that particular cell surface receptors namely the scavenger receptor CD36 and the endocannabinoid receptor CB1 are involved in the activation and regulation of the NLRP3 inflammasome and they have also been implicated in the pathogenesis of atherosclerosis. The present study aimed to investigate expression and activation levels of the NLRP3 inflammasome, the CD36 and CB1 receptors in blood samples obtained from patients with atherosclerosis at very high risk of a Major Adverse Cardiac Event (MACE) such as a heart attack. The cell signalling processes involved in NLRP3 inflammasome activation were also investigated in a THP1 in vitro model of atherosclerosis. Results to date indicate increased expression of NLRP3 in patients at very high risk of MACE and also demonstrate that THP1 macrophages require both the CD36 and CB1 receptors for optimal NLRP3 expression in response to oxidized LDL. These preliminary findings provide an insight into the mechanism of action of the NLRP3 inflammasome in atherosclerosis and prompt further exploration of this protein complex and its regulatory receptors as potential targets for prognostic and or therapeutic development in the strive towards a more personalised approach to the management of coronary artery disease., Approximately 30% of patients with epilepsy are refractory to anti-epileptic drug (AED) treatment and continue to have debilitating seizures that severely impact upon their quality of life. Exome sequencing in encephs etc has illustrated the importance of de-novo variants in the pathogenesis of rare neurological disorders. However, the contribution of de-novo mutations to pharmacoresistance in adult epilepsy is uncertain. In this study we investigated whether a trio whole exome sequencing paradigm could be applied to identify genetic causes of chronic, refractory epilepsy. We selected adult patients (n=5) with onset of seizures after 5 years of age, had failed ≥6 AEDs and were still experiencing >4 disabling seizures per month. Patients were excluded if they had a potentially ‘explanatory’ lesion on MRI. Parents were exome sequenced to identify de-novo mutations and these were assessed bioinformatically for pathogenicity. We confirmed the presence of coding de-novo mutations that were bioinformatically predicted to be functional and damaging in 3/5 patients. One of these occurred in the gene DNM1L, which was recently implicated in pharmacoresistant epilepsy (Vanstone et al. EJHG, 2015;Nov 25). This represents a potential diagnostic yield of 20% however more data is required and more trios are currently being sequenced. We have demonstrated the potential diagnostic yield of whole exome sequencing in a small number of adult patients with chronic refractory epilepsy. Identifying genetic mutations underpinning this disorder may provide new insight into the underlying biology and offers the potential for therapeutic intervention in the form of precision medicine., IgA nephropathy (IgAN) is the most common form of glomerular nephritis worldwide1. Difference in incidences between ethnicities and familial inheritance patterns indicate this is a genetic disorder. An IgAN locus on chromosome 6q22-23 was identified via linkage analysis; however the causal gene remains elusive2. We set out to identify mutations underlying familial IgAN using whole exome sequencing. DNA was collected on 25 (unaffected and affected) individuals across 6 families with IgAN. Families were chosen on the basis of having at least 2 affected members with IgAN. We carried out full exome sequencing on 12 of the affected members from these families. Depending on the pattern of inheritance in a given family, mutations that fitted a dominant, recessive or compound heterozygote model of inheritance were screened for. These variants were then filtered based on being shared between affected individuals within a family, their minor allele frequency, region, function and predicted deleterious nature. We identified a number of potential candidate mutations in these families and including a mutation in the gene COL4A5 which was previously described as pathogenic3. Mutations in COL4A5 have previously been found in individuals with Alport syndrome, a disease which is often mistaken for IgAN. We are currently working to confirm these candidate mutations via Sanger sequencing and will be screening for segregation., Atherosclerosis is a chronic inflammatory disorder that is responsible for approximately 71% of incidents of cardiovascular disease. A mathematical model of atherosclerosis has been developed, capturing the cell types and proteins involved in atheroma formation and describing the dynamics of disease progression. This is the first model of this type to be developed using open systems biology standards. We have predicted tertiary protein structures for all the proteins involved in this atherosclerosis model and all of their recorded mutations, using phase 3 sequence data obtained from the 1000 Genomes Project. By comparing the electrostatic potentials of these tertiary structures, we predict how the dynamics of atherosclerosis stratifies across population subgroups., The aim of this pilot study was to test the feasibility of carrying out a large scale study using this design to investigate whether methylation of the oxytocin receptor (OXTR) can serve as a potential biomarker for response to oxytocin administration in women during and after labour. Background Oxytocin is a nine-amino acid peptide with hormonal and neurotransmitter functions during labour and lactation. We hypothesised that a difference in methylation levels of the oxytocin receptor (OXTR) gene may impact the woman’s ability to become established in labour and her response to oxytocin administration. Method Blood samples were taken pre-birth and postnatally from 21 women and subjected to DNA methylation analysis of the OXTR gene by pyrosequencing. Methylation status of CpG sites -924 and -934 upstream from the initiation transcription site (ITS) of the OXTR gene was determined. Expression of the OXTR gene before and after birth was measured using qPCR. Global methylation levels were examined using Luminometric Methylation Assay (LUMA). Results We found both hypo and hypermethylation of OXTR promoter at CpG sites -924 and -934 in individual samples, however we observed no profound changes in overall OXTR methylation levels within the patient cohort at these CpG sites. We found a strong correlation between OXTR promoter methylation levels found in whole blood and those found in matched PMBC samples. Global methylation analysis using Luminometric Methylation Assay (LUMA) revealed no significant differences between whole blood and PMBC. Conclusions A larger sample is required to determine whether OXTR methylation status is predictive of response to oxytocin administration. Whole blood sampling is a suitable alternative for OXTR methylation analysis in a larger cohort of women undergoing labour., Background Cardiovascular disease (CVD) is the leading cause globally of morbidity and mortality. microRNAs (miRNAs) are small, non-coding RNAs which have a fundamental role in the pathology of various diseases including CVD. Circulating serum levels of miRNAs have been proposed as potentially valuable markers of heart failure, stroke, myocardial infarction and arterial hypertension, but the specific miRNAs involved and their function remains unclear. Therefore, this pilot study aims to profile miRNA expression in premature CVD patients to identify which miRNAs correlate best with hypertension. Methods The Multiplex Circulating miRNA Assay with Firefly™ Particle Technologies was used to profile 68 miRNAs on a cardiology focus panel in serum samples from 170 premature CVD patients recruited from Altnagelvin Area Hospital and screened for the C677T polymorphism in methylenetetrahydrofolate reductase, a risk factor for hypertension. Samples were collected at baseline and following intervention with riboflavin, a co-factor for MTHFR, which significantly lowers blood pressure specifically in adults with this polymorphism. Statistical analysis was used to correlate miRNA expression with blood pressure, MTHFR genotype and other relevant clinical data. Results The assay successfully measured miRNA expression in the sample set. miRNAs which expressed differentially between MTHFR genotype groups were highlighted and the functional significance of these miRNAs was assessed using bioinformatics to identify target genes involved in CVD. Conclusions The data provides further evidence that using specific miRNAs as serum markers could aid early prediction of CVD and may lead to better diagnostic modalities and therapeutic regimes., Gene-environment interactions, particularly in genes related to regulation of serotonin and neuronal function, have been implicated in the aetiology of depression. Allelic variations in the 5’ flanking transcriptional region of the serotonin transporter gene (5-HTTLPR) and higher levels of promoter DNA methylation are associated with depression. Brain derived neurotrophic factor (BDNF) plays an important role in neuronal differentiation and survival, and is also involved in regulation of serotonin. A single nucleotide polymorphism in the BDNF gene, leading to a valine to methionine substitution at codon 66 (Val66Met), and increased methylation of the BDNF promoter have also been associated with depression. The goal of this study is to determine whether length of the 5-HTTLPR, prevalence of the Val66Met polymorphism of the BDNF gene and DNA methylation in both 5-HTT and BDNF promoter regions are associated with depression in the student population. First year students provided a saliva sample for genetic analysis and completed an online mental health survey. Presence and severity of depression was determined from survey responses based on DSM-IV criteria. Length of the 5-HTTLPR was determined by PCR and gel electrophoresis and presence of the SNP at BDNF rs6265 and examined using restriction fragment length polymorphism analysis. Bisulphite-treated DNA was amplified by PCR and pyrosequencing assays used to determine methylation patterns of BDNF and SERT. Our preliminary findings suggest that genetic and epigenetic variation in the 5HTT and BDNF genes are associated with depression in the student population and may be candidate biological markers to assist in diagnosis., BACKGROUND Prostate cancer is the most common male cancer in the UK, where it kills approximately 11,000 men annually. There has been growing interest in the role played by the anaerobic bacterium Propionibacterium acnes, an important component if the skin microflora, in the aetiology of the condition via a chronic, asymptomatic infection of the prostate leading to oncogenesis. METHODS A quantitative real-time PCR (qRT-PRC) assay for retrospective detection of P. acnes in formalin-fixed paraffin embedded sections from archived prostate samples was developed. An in vitro infection model of prostate infection with P. acnes is being optimised, which should allow us to get insight into the dysregulation P. acnes infection causes in prostate epithelial cells. RESULTS A total of 81 biopsy samples, representing one or both prostate lobes, were examined from 53 patients with prostate carcinoma, versus 111 samples from 60 patients whose biopsies were histologically normal, and the assay revealed that 35% of cancerous prostate samples were positive for the presence of P. acnes, compared with only 8% of the disease-free samples (p, Oral squamous cell carcinoma (OSCC) is one of the top ten most prevalent cancers in the world. Prognosis is poor and quality of life is commonly reduced for patients who survive. OSCC is thought to progress via a premalignant stage called dysplasia. Effective treatment of dysplasia prior to malignant transformation, or the ability to more accurately predict the 10-20% of dysplasias that will progress to OSCC, is an unmet clinical need. With the aim to better understand the biology of OSCC development, and attempt to identify potential markers of early disease and therapeutic targets, we performed parallel whole exome sequencing and total RNA sequencing on 16 micro-dissected formalin-fixed paraffin embedded dysplasia and their associated OSCC. These are the largest omic analyses on matched patient samples from the oral cavity in non-HPV infected patients where all dysplasias are associated with progression to OSCC, that has been performed to date. Whole exome analysis revealed that every OSCC and adjacent associated dysplasia sample did have a common clonal ancestor, with many shared potential drivers of progression, but that there is also considerable genomic heterogeneity between associated pre-invasive and invasive disease, as seen in a previous study1. RNAseq analysis revealed differences in the immune cell signatures present at different disease stages, distinguished early events in pathogenesis from later events and identified several novel coding and non-coding candidates with potential involvement in oral dysplasia development and malignant transformation. These findings merit further investigation in a larger retrospective longitudinal study of patients with oral dysplasia., Many disorders involving tissues, which have significant energy requirements, involve mitochondrial dysfunction often due to mutations affecting the mitochondrial genome. Some such mutations can involve genes coding for subunits of complex I of the electron transport chain leading to a complex I deficiency in disorders such as Leber Hereditary Optic Neuropathy (LHON) amongst others. Mitochondrial dysfunction leads to a lack of energy production and ultimately the death of the cell. In disorders such as LHON, retinal ganglion cells (RGCs) are affected, leading to retinal dysfunction. These observations have prompted interest in exploring innovative therapeutics to modulate mitochondrial disorders involving complex I deficiency. The Farrar laboratory has explored candidate gene therapies for complex I deficiency using Ndi1, a yeast gene which is a complex I homologue. In order to test the efficacy of candidate therapies, we have developed a robust, empirical assay of mitochondrial function. Previous assays measured the level of NADH oxidation in a sample, both before and after rotenone as a measure of complex I activity. To optimally distinguish between the activity of complex I and the potential therapeutic, the assay was modified with the addition of a second inhibitor which allowed specific measurement of the therapeutic, such as Ndi1. Given that this is an in vitro assay, it enables large-scale screening of potential therapeutics and ensures only those that show strong evidence of efficacy are then tested in vivo. In combination with other quantitative assays such as Reactive Oxygen Species (ROS) generation this allows detailed evaluation of the health of mitochondria within a sample., Schizophrenia is an adult-onset mental illness with that impacts cognitive function. The largest GWAS has revealed 108 loci associated with schizophrenia risk but how variation affects genes and impacts brain function to increase risk is largely unknown. The centrosome is the microtubule organising centre of the cell and seeds the growth of the primary cilium. The disproportionate number of brain disorders associated with centrosomal genes suggests the organelle underlies normal brain and cognitive development. Schizophrenia is neurodevelopmental and cognitive deficits are a core element of the disorder. We hypothesise that some of the newly identified risk genes for schizophrenia will function in the centrosome and variants in these genes will be associated with cognitive deficits. Cross-referencing genes with centrosomal functions with genes from schizophrenia GWAS, identified six candidate genes; SDCCAG8, MAD1L1, GIGYF2, MPHOSPH9, PRKD1 and MAPK3. The effect of risk SNPs on cognition was examined using an Irish dataset of psychosis cases and controls (n=1,236) using linear regression. Among the associations identified, the SDCCAG8 risk SNP was shown to affect attribution style, a measure of social cognition (P=0.001). The MAD1L1 risk SNP was associated with poorer performance on episodic memory tasks (P=0.003). A suitable replication dataset was not available for social cognition measures. We attempted replication for episodic memory results in UK and German samples but results were non-significant. Overall, we have identified a number of schizophrenia risk genes that function in the centrosome but further larger datasets are required to establish a role for these genes in cognition., Epigenetic mechanisms are an important heritable and dynamic means of regulating various genomic functions, including gene expression to orchestrate brain development. These processes when perturbed are thought to contribute to schizophrenia (SZ). A core feature of SZ is cognitive dysfunction. GWAS have identified 108 genomic loci associated with SZ risk, containing 350 genes. My aim was to identify genes that have epigenetic functions which map to loci associated with SZ, and to test the associated SNPs for association with cognitive deficits. Risk SNPs in 8 genes: BCL11B, CHD7, EP300, EPC2, GATAD2A, KDM3B, RERE and SATB2 were analysed using an Irish dataset of psychosis cases and controls (n=1235) who had completed tests across 5 cognitive domains. Five of the eight variants had significant associations with at least one cognitive task. Strongest associations were for CHD7 (rs6984242) for IQ (p=0.001) and episodic memory (p=0.007). These results did not replicate in independent samples. We link rs6984242 to CHD7 via a long range expression quantitative trait loci (eQTL) and CHD7 has not been previously reported as a candidate risk gene for SZ. To further explore its novel association with SZ, we identified a set of 45 interacting genes and used SNPs across these genes to develop a polygenic risk score for SZ, independent of CHD7 itself. This score was tested for association with cognitive function. Significant associations(p, The relevance of nutrition and other environmental influences on epigenetic modifications including DNA methylation is a topic of considerable interest. Folate One Carbon Metabolism (FOCM) is the principal supplier of the methyl groups required for DNA methylation, giving folate status a strong biological plausibility of having an impact on an individual’s and an offspring’s DNA methylation profile at both the mitotic and meiotic level. We sought to identify DNA methylation sites in the human genome that are sensitive to folate status i.e., Folate-sensitive Differentially Methylated Regions (FS-DMR) using a folic acid intervention trial in pregnant women known as FASSTT (Folic Acid Supplementation in the Second and Third Trimesters). To minimize the amount of DNA methylation ‘noise’ due to non-folate related factors such as other environmental stimuli and individual genetic variation, we compared the DNA methylation profile of the same individual pre- and post- intervention to identify putative FS-DMR. We selected six healthy pregnant women, three from the folic acid intervention arm and three from the placebo arm of the trial. We performed MeDIP (Methylated DNA Immunoprecipitation) on all 12 samples and hybridized to a Roche Nimblegen Delux 2.1M promoter array. While we observed DNA methylation changes pre- and post- folic acid intervention in each individual, the actual DNA methylation sites were not consistent across all three individuals. Of course, it is possible that a more in-depth Next Generation Sequencing approach might yield our elusive FS-DMRs. However, the published literature to date does not appear to support such a promise., The loss of retinal ganglion cells (RGCs) is a hallmark of a number of retinopathies. There are a number of gene therapies being developed that have shown efficacy in preserving RGCs when administered using an AAV vector. Localising expression of any therapeutic to the target cell type (ganglion cell layer, GCL) would represent a significant optimisation of the approach. The packaging capacity of AAV (4.7kb) imposes a limit on the size of promoters and genes relevant for AAV-mediated gene delivery. Few GCL-specific promoter sequences have been defined of a size suitable for use in AAV-guided gene expression. Exploring this, a panel of genes was chosen with GCL-limited expression profiles. A pipeline program was developed that analysed regions upstream of these genes for sequence conservation across placental mammals (as a proxy for putative promoter function), weighted by enriched GCL expression levels. Adopting this strategy, ganglion cell promoter 1 (GCP1), demonstrating the key features outlined above, was identified. To test its function, GCP1 (2.2kb in size) was engineered into an AAV2 virus expressing EGFP. Here we demonstrate the effectiveness of GCP1 in localising EGFP expression to the GCL when administered via intravitreal injection. Furthermore, absence of EGFP expression was demonstrated when targeted towards photoreceptors via subretinal injection, verifying GCP1 tissue-specificity. Expression of AAV2.GCP1-EGFP was compared to expression from a non-specific promoter construct, AAV2.CMV-EGFP. GCP1-EGFP was shown to provide equivalent expression to CMV-EGFP in the GCL. GCP1 thus offers a tissue-specific promoter option, suitable for deployment within AAV vectors without compromising functionality., Purpose Hypoxia is a common hallmark of the tumour microenvironment. Recently we have shown the anti-androgen bicalutamide induces profound hypoxia in prostate tumours in vivo. This resulted in the promotion of epithelial to mesenchymal transition. Here we target tumour hypoxia using a novel unidirectional hypoxia-activated prodrug OCT1002 to enhance the anti-tumour effect of bicalutamide. Experimental Design The effect of OCT1002 treatment on LNCaP-luc cells was measured in normoxia and hypoxia in vitro. In vivo, tumour growth and lung metastases were measured in mice treated with bicalutamide, OCT1002 or a combination. Dorsal skin fold chambers were used to image tumour vasculature in vivo. Longitudinal genetic changes in tumours were analysed using PCR. Results Reduction of OCT1002 to its active form (OCT1001) decreased LNCaP-luc cell viability. In LNCaP-luc spheroids, OCT1002 caused increased apoptosis and decreased clonogenicity. In vivo, treatment with OCT1002 alone or with bicalutamide, showed significantly greater tumour growth control and reduced lung metastases compared to controls. Re-establishment of the tumour vasculature following bicalutamide-induced vascular collapse is inhibited by OCT1002. Significantly, the up-regulation of RUNX2 and its targets caused by bicalutamide alone were also blocked by OCT1002. Conclusions OCT1002 selectively targets hypoxic tumour cells and enhances the anti-tumour efficacy of bicalutamide. Furthermore, bicalutamide causes changing genetic profiles during treatment, with development of a more malignant genotype; OCT1002 can block this effect. This study indicates that more attention should be attached to understanding genetic changes that may occur during treatment. Early targeting of hypoxic cells with OCT1002 can provide a means of inhibiting prostate tumour growth and malignant progression., Background In prostate cancer (PCa), abnormal expression of several microRNAs (miRNAs) has been previously reported. Increasing evidence shows that aberrant epigenetic regulation is a contributing factor to their altered expression in cancer. In this study we investigate whether expression of miR-200c and miR-141 in PCa is related to the DNA methylation status of their promoter. Methods PCR analysis of miR-200c and miR-141, and CpG methylation analysis of their common promoter, was performed in PCa cell-lines and in FFPE prostate biopsy specimens. The functionality of miR-200c and miR-141 expression in prostate cancer cells was assessed by a series of in vitro bioassays. Results miR-200c and miR-141 expression correlates inversely with the methylation status of the miR-200c/miR-141 promoter in PCa cells. In PC3 cells, miR-200c and miR-141 expression is elevated by treatment with the demethylating agents suggesting their expression is linked to methylation. Expression of miR-200c and miR-141 in prostate biopsy tissue was inversely correlated with methylation in CpG sites closest to the miR-200c/miR-141 loci. Over-expression of miR-200c in PC3 cells inhibited growth and clonogenic potential, as well as inducing apoptosis. Expression of the genes DNMT3A and TET1/TET3 were down-regulated by miR-200c and miR-141 respectively. Finally, treatment with the soy isoflavone genistein caused demethylation of the promoter CpG sites closest to the miR-200c/miR-141 loci resulting in increased miR-200c expression. Conclusions Our findings provide evidence that miR-200c and miR-141 are under epigenetic regulation in PCa cells. Profiling their expression and methylation status may have potential in the improved diagnosis and prognosis of PCa., Increasingly accurate surveys of human health throughout the life course has led experts to propose that stresses on the child while still in the mother’s womb can affect the individual’s health much later in life. Such long-term effects on health are thought to be mediated by a semi-permanent trace on the genes of the affected person called an epigenetic mark. Epigenetic mechanisms, such as DNA methylation, are dynamic during pregnancy whereby epigenetic marks are seeded which persist throughout the lifetime of the developing child. It has been suggested that these patterns may be altered by the mother’s diet, particularly folate – a key component in the DNA methylation cycle. Currently, mothers are universally recommended to supplement their diet with 400μg folic acid/day as a preventative measure against neural tube defects in the offspring prior to and during the first trimester. However, there remains no clinical recommendation as to whether mothers should continue supplementation during the final two trimesters and the potentially heritable effects on DNA methylation. Observational studies have suggested that folate-rich maternal diets are associated with changes in DNA methylation of the child during this period of gestation. We present here the results of a randomised control trial (FASSTT study) examining the effects of folic acid supplementation in late gestation (week 12 onwards) on DNA methylation of several gene classes in offspring cord blood samples. We report small but significant sex-specific differences between the two intervention groups. These preliminary results indicate that folic acid supplementation throughout pregnancy may exert significant effects on cord blood DNA methylation., Introduction New-onset diabetes after transplantation (NODAT) is a common complication of kidney transplantation which increases risk of subsequent graft failure, cardiovascular complications and death. NODAT is defined as the new requirement for oral hypoglycaemic agents or insulin as a result of hyperglycaemia after renal transplant. The first genome wide association study (GWAS) for NODAT was published by our group in 2014; seven of the eight top-ranked, common SNPs are implicated in β-cell apoptosis. Methods To further understand the genetic architecture of the NODAT phenotype we used whole exome sequencing for 134renal transplant recipients from a Northern Ireland renal transplant cohort. We sequenced 53 individuals with NODAT (cases)and 81 transplant recipients without NODAT (controls). Library preparation was performed using the Ion TargetSeq™ Exome Kit with samples sequenced on an Ion Torrent Proton sequencer. TheIon OneTouch 2 for emulsion PCR and Ion Enrichment System were used. Association analysis was performed using PLINK Version 1.9 to identify variants associated with NODAT (with age and weight at transplant included in the regression model). Results Following appropriate quality control, initial analysis identified 6 variants nominally associated with NODAT (Ptrend, The Irish Traveller community has a high incidence of autosomal recessive (AR) disorders due to consanguinity. The Division of Molecular Genetics at the DCG offers genetic testing, primarily to members of this community, for five specific pathogenic mutations found in five AR disorders. The pathogenic mutations are detected by bi-directional Sanger sequencing and the service includes: Gene Disorder/ Disease Phenotype LARS (leucyl-tRNA synthetase) Infantile Liver Failure Syndrome 1 (ILFS1) Infantile hepatopathy with failure to thrive (FTT) and developmental delay. MCM4 (minichromosome maintenance 4) Natural Killer Cell & Glucocorticoid Deficiency with DNA Repair Defect (NKGCD) FTT, adrenocorticotropin hormone (ACTH) resistance, familial glucocorticoid deficiency (FGD), mosaic Fanconi anaemia and recurrent infections due to NK cell deficiency. STRA6 (stimulated by retinoic acid 6 gene) Autosomal recessive isolated colobomatous microanopthalmia (MCOPS9) Microphthalmia, anophthalmia, coloboma.Specific STRA6 mutation can also cause the Matthew-Wood syndrome [anophthalmia/ severe microphthalmia, with pulmonary hypoplasia/ aplasia] LEPRE1 (Leucine-and proline-enriched proteoglycan 1)syn. PH31(prolyl-3-hydroxylase-1) Type VIII Osteogenesis Imperfecta, Variable phenoptype of bone fragility, susceptibility to fracture, short stature, bowing of the long bones and can be perinatally lethal. ATP8B1 (ATPase, Class I, Type 8B, Member1) Progressive Familial Intrahepatic Cholestasis type 1 (PFIC1) syn. Byler disease Hepatic and systemic accumulation of bile acids, hepatic fibrosis, end-stage liver disease and growth retardation. This study will detail (1) the service offered to users, (2) an audit of the test requests received over the last two years, (3) the challenges encountered in offering this unique service and (4) some interesting family pedigrees., Background Hypoxia in prostate tumours has been linked with promotion of disease progression and metastasis. miR-210 is a microRNA which is apparently affected by hypoxia, but this relationship has not been extensively studied in a prostate cancer setting. Therefore, in this study, we investigate the link between hypoxia and miR-210 in prostate cancer cells. Methods We have used 2D and 3D cell prostate cell models of hypoxia to investigate the functionality of miR-210. Expression levels of miR-210 have been measured by qPCR and functional bioassays used to examine its effect on prostate cell behaviour. Target genes have been identified and bioinformatic analysis has been employed to investigate a clinical significance for miR-210 in prostate cancer. Results miR-210 is induced by hypoxia in prostate cancer cell-lines. Over-expression of miR-210 impacts upon target genes, including SP1 and TPD52, which in turns affects cell proliferation. Data-mining of online repositories of clinical data and bioinformatic analysis of miR-210 cellular networks reveal that miR-210 plays a key role in a number of important cell processes, the dysregulation of which can lead to development of prostate cancer. Conclusions We propose that miR-210 could be an important microRNA in the pathogenesis of prostate cancer and has potential as a biomarker in this disease.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P

BACKGROUND: Sequencing studies have pointed to the involvement in schizophrenia of rare coding variants in neuronally expressed genes, including activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-D-aspartate receptor (NMDAR) complexes; however, larger samples are required to reveal novel genes and specific biological mechanisms. METHODS: We sequenced 187 genes, selected for prior evidence of association with schizophrenia, in a new dataset of 5207 cases and 4991 controls. Included among these genes were members of ARC and NMDAR postsynaptic protein complexes, as well as voltage-gated sodium and calcium channels. We performed a rare variant meta-analysis with published sequencing data for a total of 11,319 cases, 15,854 controls, and 1136 trios. RESULTS: While no individual gene was significantly associated with schizophrenia after genome-wide correction for multiple testing, we strengthen the evidence that rare exonic variants in the ARC (p = 4.0 × 10-4) and NMDAR (p = 1.7 × 10-5) synaptic complexes are risk factors for schizophrenia. In addition, we found that loss-of-function variants and missense variants at paralog-conserved sites were enriched in voltage-gated sodium channels, particularly the alpha subunits (p = 8.6 × 10-4). CONCLUSIONS: In one of the largest sequencing studies of schizophrenia to date, we provide novel evidence that multiple voltage-gated sodium channels are involved in schizophrenia pathogenesis and confirm the involvement of ARC and NMDAR postsynaptic complexes. ispartof: BIOLOGICAL PSYCHIATRY vol:85 issue:7 pages:554-562 ispartof: location:United States status: published

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.

Objective: Genome‐wide association studies (GWAS) have identified over 30 susceptibility loci associated with Alzheimer's disease (AD). Using AD GWAS data from the International Genomics of Alzheimer's Project (IGAP), Polygenic Risk Score (PRS) was successfully applied to predict life time risk of AD development. A recently introduced Polygenic Hazard Score (PHS) is able to quantify individuals with age‐specific genetic risk for AD. The aim of this study was to quantify the age‐specific genetic risk for AD with PRS and compare the results generated by PRS with those from PHS. Methods: Quantification of individual differences in age‐specific genetic risk for AD identified by the PRS, was performed with Cox Regression on 9903 (2626 cases and 7277 controls) individuals from the Genetic and Environmental Risk in Alzheimer's Disease consortium (GERAD). Polygenic Hazard Scores were generated for the same individuals. The age‐specific genetic risk for AD identified by the PRS was compared with that generated by the PHS. This was repeated using varying SNPs P‐value thresholds for disease association. Results: Polygenic Risk Score significantly predicted the risk associated with age at AD onset when SNPs were preselected for association to AD at P ≤ 0.001. The strongest effect (B = 0.28, SE = 0.04, P = 2.5 × 10−12) was observed for PRS based upon genome‐wide significant SNPs (P ≤ 5 × 10−8). The strength of association was weaker with less stringent SNP selection thresholds. Interpretation: Both PRS and PHS can be used to predict an age‐specific risk for developing AD. The PHS approach uses SNP effect sizes derived with the Cox Proportional Hazard Regression model. When SNPs were selected based upon AD GWAS case/control P ≤ 10−3, we found no advantage of using SNP effects sizes calculated with the Cox Proportional Hazard Regression model in our study. When SNPs are selected for association with AD risk at P > 10−3, the age‐specific risk prediction results are not significant for either PRS or PHS. However PHS could be more advantageous than PRS of age specific AD risk predictions when SNPs are prioritized for association with AD age at onset (i.e., powerful Cox Regression GWAS study).

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We investigated the extent to which familiality of schizophrenia is associated with enrichment for common risk variants detectable in a large GWAS. We analyzed single nucleotide polymorphism (SNP) data for cases reporting a family history of psychotic illness (N=978), cases reporting no such family history (N=4,503), and unscreened controls (N=8,285) from the Psychiatric Genomics Consortium (PGC1) study of schizophrenia. We used a multinomial logistic regression approach with model-fitting to detect allelic effects specific to either family history subgroup. We also considered a polygenic model, in which we tested whether family history positive subjects carried more schizophrenia risk alleles than family history negative subjects, on average. Several individual SNPs attained suggestive but not genome-wide significant association with either family history subgroup. Comparison of genome-wide polygenic risk scores based on GWAS summary statistics indicated a significant enrichment for SNP effects among family history positive compared to family history negative cases (Nagelkerke's R-2=0.0021; P=0.00331; P-value threshold

IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.

Background Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. Methods We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). Results Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with rg estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98–1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11–1.18], p = 1.5E-15). Conclusions Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence.

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (h(g)(2)) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of h(g)(2) from imputed SNPs (5.1 x enrichment; p = 3.7 x 10(-17)) and 38% (SE = 4%) of h(g)(2) from genotyped SNPs (1.6 x enrichment, p = 1.0 x 10(-4)). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained

IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424)were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition.We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1%to 3%of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2%using the polygenic score only to 4.8%(P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score. © 2014 American Medical Association. All rights reserved.

We and others have previously reported linkage to schizophrenia on chromosome 10q25-q26 but, to date, a susceptibility gene in the region has not been identified. We examined data from 3606 single-nucleotide polymorphisms (SNPs) mapping to 10q25-q26 that had been typed in a genome-wide association study (GWAS) of schizophrenia (479 UK cases/2937 controls). SNPs with P

BACKGROUND: We performed a genome-wide association study (GWAS) to identify common risk variants for schizophrenia. METHODS: The discovery scan included 1606 patients and 1794 controls from Ireland, using 6,212,339 directly genotyped or imputed single nucleotide polymorphisms (SNPs). A subset of this sample (270 cases and 860 controls) was subsequently included in the Psychiatric GWAS Consortium-schizophrenia GWAS meta-analysis. RESULTS: One hundred eight SNPs were taken forward for replication in an independent sample of 13,195 cases and 31,021 control subjects. The most significant associations in discovery, corrected for genomic inflation, were (rs204999, p combined = 1.34 × 10(-9) and in combined samples (rs2523722 p combined = 2.88 × 10(-16)) mapped to the major histocompatibility complex (MHC) region. We imputed classical human leukocyte antigen (HLA) alleles at the locus; the most significant finding was with HLA-C*01:02. This association was distinct from the top SNP signal. The HLA alleles DRB1*03:01 and B*08:01 were protective, replicating a previous study. CONCLUSIONS: This study provides further support for involvement of MHC class I molecules in schizophrenia. We found evidence of association with previously reported risk alleles at the TCF4, VRK2, and ZNF804A loci.

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Rationale: Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment. Objectives: To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment. Methods: Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation. Results: Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p = 0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p = 0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants. Conclusions: The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects. © 2014 The Author(s).

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants., Imputation uses genotype information from SNP arrays to infer the genotypes of missing markers. Here, the authors show that an imputation reference panel derived from whole-genome sequencing of 3,781 samples from the UK10K project improves the imputation accuracy and coverage of low frequency variants compared to existing methods.

BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder. NIMH R01 MH077139 R01 MH095034 Stanley Center for Psychiatric Research Sylvan Herman Foundation Friedman Brain Institute at the Mount Sinai School of Medicine Karolinska Institutet, Karolinska University Hospital Swedish Research Council Swedish County Council Soderstrom Konigska Foundation Netherlands Scientific Organization NWO 645-000-003 info:eu-repo/grantAgreement/EC/FP7/223423 Danish Strategic Research Council H. Lundbeck A/S Faculty of Health Sciences at Aarhus University Lundbeck Foundation Stanley Research Foundation Wellcome Trust 085475/B/08/Z 085475/Z/08/Z

BACKGROUND: Thousands of common single nucleotide polymorphisms (SNPs) are weakly associated with schizophrenia. It is likely that subsets of disease-associated SNPs are associated with distinct heritable disease-associated phenotypes. Therefore, we examined the shared genetic susceptibility modulating schizophrenia and brain volume. METHODS: Odds ratios for genome-wide SNP data were calculated in the sample collected by the Psychiatric Genome-wide Association Study Consortium (8690 schizophrenia patients and 11,831 control subjects, excluding subjects from the present study). These were used to calculate individual polygenic schizophrenia (risk) scores in an independent sample of 152 schizophrenia patients and 142 healthy control subjects with available structural magnetic resonance imaging scans. RESULTS: In the entire group, the polygenic schizophrenia score was significantly associated with total brain volume (R2 = .048, p = 1.6 × 10(-4)) and white matter volume (R2 = .051, p = 8.6 × 10(-5)) equally in patients and control subjects. The number of (independent) SNPs that substantially influenced both disease risk and white matter (n = 2020) was much smaller than the entire set of SNPs that modulated disease status (n = 14,751). From the set of 2020 SNPs, a group of 186 SNPs showed most evidence for association with white matter volume and an explorative functional analysis showed that these SNPs were located in genes with neuronal functions. CONCLUSIONS: These results indicate that a relatively small subset of schizophrenia genetic risk variants is related to the (normal) development of white matter. This, in turn, suggests that disruptions in white matter growth increase the susceptibility to develop schizophrenia.

Item does not contain fulltext OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. METHOD: The authors performed a genome-wide analysis of large, rare CNVs (100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. CONCLUSIONS: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5-3.6), this locus could be an important contributor to ADHD etiology. 01 februari 2012

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations(1). Genome-wide association studies and subsequent meta-analyses of these two diseases(2,3) as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy(4), in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases(5). Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.