Genome-wide association study identifies five new schizophrenia loci

We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10 -11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10 -9), ANK3 (rs10994359, P = 2.5 × 10 -8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10 -9).

Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only ~45% of FJHN probands, indicating the involvement of other genetic loci in ~55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a ~5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a ~5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p= 2·4×10-8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10-8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10-4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix. © 2011 Elsevier Ltd.

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10-10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10-9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10-14, OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10-14, OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. © 2011 Nature America, Inc. All rights reserved.

Genetics and genomics of ankylosing spondylitis

Ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the pathogenesis of which is poorly understood. The mechanism by which the main gene for the disease, HLA-B27, leads to AS is unknown. Genetic and genomic studies have demonstrated involvement of the interleukin-23 (IL-23) signaling pathway in AS, a finding which has stimulated much new research into the disease and has led to therapeutic trials. Several other genes and genetic regions, including further major histocompatibility complex (MHC) and non-MHC loci, have been shown to be involved in the disease, but it is not clear yet how they actually induce the condition. These findings have shown that there is a strong genetic overlap between AS and Crohn's disease in particular, although there are also major differences in the genes involved in the two conditions, presumably explaining their different presentations. Genomic and proteomic studies are in an early phase but have potential both as diagnostic/prognostic tools and as a further hypothesis-free tool to investigate AS pathogenesis. Given the slow progress in studying the mechanism of association of HLA-B27 with AS, these may prove to be more fruitful approaches to investigating the pathogenesis of the disease. © 2009 John Wiley & Sons A/S.

A genome-wide asociation study identifies new psoriasis susceptibility loci and an interaction betwEn HLA-C and ERAP1

To identify new susceptibility loci for psoriasis, we undertOk a genome-wide asociation study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified asociations at eight previously unreported genomic loci. Seven loci harbored genes with recognized iMune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These asociations were replicated in 9,079 European samples (six loci with a combined P < 5-10 -8 and two loci with a combined P < 5-10-7). We also report compeLing evidence for an interaction betwEn the HLA-C and ERAP1 loci (combined P = 6.95-10-6). ERAP1 plays an important role in MHC claS I peptide proceSing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk aLele. Our findings implicate pathways that integrate epidermal barrier dysfunction with iNate and adaptive iMune dysregulation in psoriasis pathogenesis.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P 10 800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10 19) and 21q22 (rs2242944; P = 8.3 × 10 20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10 8) and IL1R2 (rs2310173; P = 4.8 × 10 7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10 14) and ERAP1 (rs27434; P = 5.3 × 10 12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility. © 2010 Nature America, Inc. All rights reserved.

Epidemiology of ankylosing spondylitis: IGAS 2009

The International Genetics of Ankylosing Spondylitis (IGAS) meeting was held in Houston, Texas, July 25, 2009. Sixteen investigators from Asia, Australia, Europe, and North and South America presented the status of their respective cohorts of patients with ankylosing spondylitis (AS). They also reviewed a proposal to examine their patients by single-nucleotide polymorphism (SNP) genotyping on an Illumina Infinium microarray SNP genotyping chip in a case-control cohort exceeding 12,000 samples. This chip will type 200,000 SNP selected from the most strongly associated variants identified in genome-wide association studies of inflammatory diseases, including inflammatory bowel disease, psoriasis, and ankylosing spondylitis.

Predominant association of HLA-B*2704 with ankylosing spondylitis in Chinese Han patients

The HLA-B27 subtypes have a varied racial and ethnic prevalence throughout the world. However, the association of B27-subtypes with ankylosing spondylitis (AS) in the mainland China is unknown. To determine the association of B27-subtypes with AS in the Mainland Chinese Han population, a total of unrelated 153 patients with AS were enrolled in a large case-control association study, and 1545 unrelated, healthy, ethnically matched blood donors were included as controls. The genotyping of B27 and its subtypes was performed using the polymerase chain reaction with sequence specific primers (PCR-SSP). A total of 130 (84.97%) AS patients and 61 (3.95%) healthy controls were B27 positive. Three B27-subtypes, B*2704, B*2705 and B*2710, were further identified, of which both B*2704 and B*2705 were strongly AS associated. B*2710 was only detected in one AS patient and two other healthy controls. Considering only B27-positive cases and controls, a statistically different frequency of B27-subtypes was observed, with an over-representation of B*2704 (P = 0.018). B*2704 was clearly more strongly associated than B*2705 with AS [odds ratio (OR) = 2.4, P = 0.011]. Furthermore, a combined analysis including three previous studies of B27-subtype distributions in Chinese AS cases confirmed the stronger association of B*2704 with AS than B*2705 (OR = 2.5, P = 0.00094).

Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series

Objectives. It has been shown previously that IL-23R variants are associated with AS. We conducted an extended analysis in the UK population and a meta-analysis with the previously published studies, in order to refine these IL-23R associations with AS. Methods. The UK case-control study included 730 new cases and 1331 healthy controls. In the extended study, the 730 cases were combined with 1088 published cases. Allelic associations were analysed using contingency tables. In the meta-analysis, 3482 cases and 3150 controls from four different published studies and the new UK cases were combined. DerSimonian-Laird test was used to calculate random effects pooled odds ratios (ORs). Results. In the UK case-control study with new cases, four of the eight SNPs showed significant associations, whereas in the extended UK study, seven of the eight IL-23R SNPs showed significant associations (P < 0.05) with AS, maximal with rs11209032 (P < 10-5, OR 1.3), when cases with IBD and/or psoriasis were excluded. The meta-analysis showed significant associations with all eight SNPs; the strongest associations were again seen not only with rs11209032 (P = 4.06 × 10-9, OR ∼1.2) but also with rs11209026 (P < 10-10, OR ∼0.6). Conclusions. IL-23R polymorphisms are clearly associated with AS, but the primary causal association(s) is(are) still not established. These polymorphisms could contribute either increased or decreased susceptibility to AS; functional studies will be required for their full evaluation. Additionally, observed stronger associations with SNPs rs11209026 and rs11465804 upon exclusion of IBD and/or psoriasis cases may represent an independent association with AS. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.

Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P 1 × 10 5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10 17), 16q22 (CDH1 and CDH3; P = 2.8 × 10 8) and 7q31 (LAMB1; P = 3.0 × 10 8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis. © 2009 Nature America, Inc. All rights reserved.

Toll-like receptor 4 and CD14 polymorphisms in ankylosing spondylitis: Evidence of a weak association in finns

Objective To investigate the association of CD14 and Toll-like receptor (TLR4) with ankylosing spondylitis (AS). Methods A promoter variant in CD14 and 2 coding polymorphisms in TLR4 were investigated in UK and Finnish families with AS and in a UK case-control study. A metaanalysis of published TLR4 and CD14 studies was performed. Results In the Finnish study the CD74-260bp T variant showed an association (p = 0.006), and the common 2-marker TLR4 haplotype showed a weak association (global p = 0.03), with AS. No associations were seen in the UK based studies or in the metaanalyses. Conclusion CD14 and TLR4 showed an association with AS in the Finns only.

Fine mapping of the MHC Class III region demonstrates association of AIF1 and rheumatoid arthritis

Objective. The heritability of RA has been estimated to be ∼55%, of which the MHC contributes about one-third. HLA-DRB1 alleles are strongly associated with RA, but it is likely that significant non-DRB1 MHC genetic susceptibility factors are involved. Previously, we identified two three-marker haplotypes in a 106-kb region in the MHC class III region immediately centromeric to TNF, which are strongly associated with RA on HLA-DRB1*0404 haplotypes. In the present study, we aimed to refine these associations further using a combination of genotyping and gene expression studies. Methods. Thirty-nine nucleotide polymorphisms (SNPs) were genotyped in 95 DRB1*0404 carrying unrelated RA cases, 125 DRB1*0404 - carrying healthy controls and 87 parent-case trio RA families in which the affected child carried HLA-DRB1*04. Quantitative RT-PCR was used to assess the expression of the positional candidate MHC class III genes APOM, BAT2, BAT3, BAT4, BAT5, AIF1, C6orf47, CSNK2β and LY6G5C, and the housekeeper genes, hypoxanthine-guanine phosphoribosyltransferase (HPRT) and β2-microglobulin (B2M) in 31 RA cases and 21 ethnically, age- and sex-matched healthy controls. Synovial membrane specimens from RA, PsA and OA cases were stained by an indirect immunoperoxidase technique using a mouse-anti-human AIF1 monoclonal antibody. Results. Association was observed between RA and single markers or two marker haplotypes involving AIF1, BAT3 and CSNK. AIF1 was also significantly overexpressed in RA mononuclear cells (1.5- to 1.9-fold difference, P = 0.02 vs HPRT, P = 0.002 vs B2M). AIF1 protein was clearly expressed by synovial macrophages in all the inflammatory synovial samples in contrast to the non-inflammatory OA samples. Conclusions. The results of the genotyping and expression studies presented here suggest a role for AIF1 in both the aetiology and pathogenesis of RA.

Developments in psoriasis and psoriatic arthritis

Psoriasis and psoriatic arthritis are common conditions for which treatment options have until recently been extremely limited. Recent advances in our understanding of the immunology and genetics underlying these conditions have been rapid, and have contributed to the development of new therapies for these diseases. This article discusses the current state of the art in our understanding of the aetiopathogenesis of psoriasis and psoriatic arthritis, and current therapies for the diseases.