CNV-ClinViewer: enhancing the clinical interpretation of large copy-number variants online.

MOTIVATION: Pathogenic copy-number variants (CNVs) can cause a heterogeneous spectrum of rare and severe disorders. However, most CNVs are benign and are part of natural variation in human genomes. CNV pathogenicity classification, genotype-phenotype analyses, and therapeutic target identification are challenging and time-consuming tasks that require the integration and analysis of information from multiple scattered sources by experts. RESULTS: Here, we introduce the CNV-ClinViewer, an open-source web application for clinical evaluation and visual exploration of CNVs. The application enables real-time interactive exploration of large CNV datasets in a user-friendly designed interface and facilitates semi-automated clinical CNV interpretation following the ACMG guidelines by integrating the ClassifCNV tool. In combination with clinical judgment, the application enables clinicians and researchers to formulate novel hypotheses and guide their decision-making process. Subsequently, the CNV-ClinViewer enhances for clinical investigators' patient care and for basic scientists' translational genomic research. AVAILABILITY AND IMPLEMENTATION: The web application is freely available at https://cnv-ClinViewer.broadinstitute.org and the open-source code can be found at https://github.com/LalResearchGroup/CNV-clinviewer.

Exploring Paleogene Tibet's warm temperate environments through target enrichment and phylogenetic niche modelling of Himalayan spiny frogs (Paini, Dicroglossidae).

The Cenozoic topographic development of the Himalaya-Tibet orogen (HTO) substantially affected the paleoenvironment and biodiversity patterns of High Asia. However, concepts on the evolution and paleoenvironmental history of the HTO differ massively in timing, elevational increase and sequence of surface uplift of the different elements of the orogen. Using target enrichment of a large set of transcriptome-derived markers, ancestral range estimation and paleoclimatic niche modelling, we assess a recently proposed concept of a warm temperate paleo-Tibet in Asian spiny frogs of the tribe Paini and reconstruct their historical biogeography. That concept was previously developed in invertebrates. Because of their early evolutionary origin, low dispersal capacity, high degree of local endemism, and strict dependence on temperature and humidity, the cladogenesis of spiny frogs may echo the evolution of the HTO paleoenvironment. We show that diversification of main lineages occurred during the early to Mid-Miocene, while the evolution of alpine taxa started during the late Miocene/early Pliocene. Our distribution and niche modelling results indicate range shifts and niche stability that may explain the modern disjunct distributions of spiny frogs. They probably maintained their (sub)tropical or (warm)temperate preferences and moved out of the ancestral paleo-Tibetan area into the Himalaya as the climate shifted, as opposed to adapting in situ. Based on ancestral range estimation, we assume the existence of low-elevation, climatically suitable corridors across paleo-Tibet during the Miocene along the Kunlun, Qiangtang and/or Gangdese Shan. Our results contribute to a deeper understanding of the mechanisms and processes of faunal evolution in the HTO.

Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes.

Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain versus loss-of-channel function. In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.

Benchmarking of univariate pleiotropy detection methods applied to epilepsy.

Pleiotropy is a widespread phenomenon that may increase insight into the etiology of biological and disease traits. Since genome-wide association studies frequently provide information on a single trait only, only univariate pleiotropy detection methods are applicable, with yet unknown comparative performance. Here, we compared five such methods with respect to their ability to detect pleiotropy, including meta-analysis, ASSET, conditional false discovery rate (cFDR), cross-phenotype Bayes (CPBayes), and pleiotropic analysis under the composite null hypothesis (PLACO), by performing extended computer simulations that varied the underlying etiological model for pleiotropy for a pair of traits, including the number of causal variants, degree of traits' overlap, effect sizes as well as trait prevalence, and varying sample sizes. Our results indicate that ASSET provides the best trade-off between power and protection against false positives. We then applied ASSET to a previously published International League Against Epilepsy (ILAE) consortium data set on complex epilepsies, comprising genetic generalized epilepsy and focal epilepsy cases and corresponding controls. We identified a novel candidate locus at 17q21.32 and confirmed locus 2q24.3, previously identified to act pleiotropically on both epilepsy subtypes by a mega-analysis. Functional annotation, tissue-specific expression, and regulatory function analysis as well as Bayesian colocalization analysis corroborated this result, rendering 17q21.32 a worthwhile candidate for follow-up studies on pleiotropy in epilepsies.

A Rare Variant Nonparametric Linkage Method for Nuclear and Extended Pedigrees with Application to Late-Onset Alzheimer Disease via WGS Data.

To analyze family-based whole-genome sequence (WGS) data for complex traits, we developed a rare variant (RV) non-parametric linkage (NPL) analysis method, which has advantages over association methods. The RV-NPL differs from the NPL in that RVs are analyzed, and allele sharing among affected relative-pairs is estimated only for minor alleles. Analyzing families can increase power because causal variants with familial aggregation usually have larger effect sizes than those underlying sporadic diseases. Differing from association analysis, for NPL only affected individuals are analyzed, which can increase power, since unaffected family members can be susceptibility variant carriers. RV-NPL is robust to population substructure and admixture, inclusion of nonpathogenic variants, as well as allelic and locus heterogeneity and can readily be applied outside of coding regions. In contrast to analyzing common variants using NPL, where loci localize to large genomic regions (e.g., >50 Mb), mapped regions are well defined for RV-NPL. Using simulation studies, we demonstrate that RV-NPL is substantially more powerful than applying traditional NPL methods to analyze RVs. The RV-NPL was applied to analyze 107 late-onset Alzheimer disease (LOAD) pedigrees of Caribbean Hispanic and European ancestry with WGS data, and statistically significant linkage (LOD ≥ 3.8) was found with RVs in PSMF1 and PTPN21 which have been shown to be involved in LOAD etiology. Additionally, nominally significant linkage was observed with RVs in ABCA7, ACE, EPHA1, and SORL1, genes that were previously reported to be associated with LOAD. RV-NPL is an ideal method to elucidate the genetic etiology of complex familial diseases.

Distinct genetic variation and heterogeneity of the Iranian population.

Iran, despite its size, geographic location and past cultural influence, has largely been a blind spot for human population genetic studies. With only sparse genetic information on the Iranian population available, we pursued its genome-wide and geographic characterization based on 1021 samples from eleven ethnic groups. We show that Iranians, while close to neighboring populations, present distinct genetic variation consistent with long-standing genetic continuity, harbor high heterogeneity and different levels of consanguinity, fall apart into a cluster of similar groups and several admixed ones and have experienced numerous language adoption events in the past. Our findings render Iran an important source for human genetic variation in Western and Central Asia, will guide adequate study sampling and assist the interpretation of putative disease-implicated genetic variation. Given Iran's internal genetic heterogeneity, future studies will have to consider ethnic affiliations and possible admixture.

Exome sequencing utility in defining the genetic landscape of hearing loss and novel-gene discovery in Iran.

Hearing loss (HL) is one of the most common sensory defects affecting more than 466 million individuals worldwide. It is clinically and genetically heterogeneous with over 120 genes causing non-syndromic HL identified to date. Here, we performed exome sequencing (ES) on a cohort of Iranian families with no disease-causing variants in known deafness-associated genes after screening with a targeted gene panel. We identified likely causal variants in 20 out of 71 families screened. Fifteen families segregated variants in known deafness-associated genes. Eight families segregated variants in novel candidate genes for HL: DBH, TOP3A, COX18, USP31, TCF19, SCP2, TENM1, and CARMIL1. In the three of these families, intrafamilial locus heterogeneity was observed with variants in both known and novel candidate genes. In aggregate, we were able to identify the underlying genetic cause of HL in nearly 30% of our study cohort using ES. This study corroborates the observation that high-throughput DNA sequencing in populations with high rates of consanguineous marriages represents a more appropriate strategy to elucidate the genetic etiology of heterogeneous conditions such as HL.

Analysis of single nucleotide polymorphisms in chronic beryllium disease.

Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.

A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.

Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10-8. As a proof of principle, we demonstrated correlation of the high-risk genotype at the statistically most strongly associated variant with decreased secretion of the soluble WNT-antagonist SFRP4, in surgical specimen-derived DD myofibroblasts. These results highlight important pathways involved in the pathogenesis of fibrosis, including WNT signaling, extracellular matrix modulation, and inflammation. In addition, many associated loci contain genes that were hitherto unrecognized as playing a role in fibrosis, opening up new avenues of research that may lead to novel treatments for DD and fibrosis more generally. DD represents an ideal human model disease for fibrosis research.

Pathway-induced allelic spectra of diseases in the presence of strong genetic effects.

Complex diseases are frequently modeled as following an additive model that excludes both intra- and inter-locus interaction, while at the same time reports on non-additive biological structures are ample, prominently featuring numerous metabolic and signaling pathways. Using extensive forward population simulations, we explored the impact of three basic pathway motifs on the relationship between epidemiological parameters, including disease prevalence, relative risk, sibling recurrence risk as well as causal variant number and allele frequency. We found that some but not all pathway motifs can shift the relationships between these parameters in comparison to the classical additive liability threshold model. The strongest deviations were observed with linear, cascade-like motifs that form an integral part of many reported pathways. We also modeled maturity-onset diabetes of the young (MODY) as a combination of different basic pathway motifs and observed a good concordance in epidemiological parameter values between our simulated data under this model and those reported in the literature. Given the widespread nature of pathways, including those in the etiology of human diseases, our results re-emphasize the need for non-additive interaction modeling of genetic variants to become an additional standard approach in analyzing human genetic data.

Guideline-based and bioinformatic reassessment of lesion-associated gene and variant pathogenicity in focal human epilepsies.

OBJECTIVE: Increasing availability of surgically resected brain tissue from patients with focal epilepsy and focal cortical dysplasia or low-grade glioneuronal tumors has fostered large-scale genetic examination. However, assessment of pathogenicity of germ line and somatic variants remains difficult. Here, we present a state-of-the-art evaluation of reported genes and variants associated with epileptic brain lesions. METHODS: We critically reevaluated the pathogenicity for all neuropathology-associated variants reported to date in the PubMed and ClinVar databases, including 101 neuropathology-associated missense variants encompassing 11 disease-related genes. We assessed gene variant tolerance and classified all identified missense variants according to guidelines from the American College of Medical Genetics and Genomics (ACMG). We further extended the bioinformatic variant prediction by introducing a novel gene-specific deleteriousness ranking for prediction scores. RESULTS: Application of ACMG guidelines and in silico gene variant tolerance analysis classified only seven of 11 genes to be likely disease-associated according to the reported disease mechanism, whereas 61 (60.4%) of 101 variants of those genes were classified as of uncertain significance, 37 (36.6%) as being likely pathogenic, and 3 (3%) as being pathogenic. SIGNIFICANCE: We concluded that the majority of neuropathology-associated variants reported to date do not have enough evidence to be classified as pathogenic. Interpretation of lesion-associated variants remains challenging, and application of current ACMG guidelines is recommended for interpretation and prediction.

Revisiting the male genetic landscape of China: a multi-center study of almost 38,000 Y-STR haplotypes.

China has repeatedly been the subject of genetic studies to elucidate its prehistoric and historic demography. While some studies reported a genetic distinction between Northern and Southern Han Chinese, others showed a more clinal picture of small differences within China. Here, we investigated the distribution of Y chromosome variation along administrative as well as ethnic divisions in the mainland territory of the People's Republic of China, including 28 administrative regions and 19 recognized Chinese nationalities, to assess the impact of recent demographic processes. To this end, we analyzed 37,994 Y chromosomal 17-marker haplotype profiles from the YHRD database with respect to forensic diversity measures and genetic distance between groups defined by administrative boundaries and ethnic origin. We observed high diversity throughout all Chinese provinces and ethnicities. Some ethnicities, including most prominently Kazakhs and Tibetans, showed significant genetic differentiation from the Han and other groups. However, differences between provinces were, except for those located on the Tibetan plateau, less pronounced. This discrepancy is explicable by the sizeable presence of Han speakers, who showed high genetic homogeneity all across China, in nearly all studied provinces. Furthermore, we observed a continuous genetic North-South gradient in the Han, confirming previous reports of a clinal distribution of Y chromosome variation and being in notable concordance with the previously observed spatial distribution of autosomal variation. Our findings shed light on the demographic changes in China accrued by a fast-growing and increasingly mobile population.

Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation.

OBJECTIVE: Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination-known as infantile convulsions and paroxysmal choreoathetosis (ICCA)-are related autosomal dominant diseases. PRRT2 (proline-rich transmembrane protein 2 gene) has been identified as the major gene in all 3 conditions, found to be mutated in 80 to 90% of familial and 30 to 35% of sporadic cases. METHODS: We searched for the genetic defect in PRRT2-negative, unrelated families with BFIS or ICCA using whole exome or targeted gene panel sequencing, and performed a detailed cliniconeurophysiological workup. RESULTS: In 3 families with a total of 16 affected members, we identified the same, cosegregating heterozygous missense mutation (c.4447G>A; p.E1483K) in SCN8A, encoding a voltage-gated sodium channel. A founder effect was excluded by linkage analysis. All individuals except 1 had normal cognitive and motor milestones, neuroimaging, and interictal neurological status. Fifteen affected members presented with afebrile focal or generalized tonic-clonic seizures during the first to second year of life; 5 of them experienced single unprovoked seizures later on. One patient had seizures only at school age. All patients stayed otherwise seizure-free, most without medication. Interictal electroencephalogram (EEG) was normal in all cases but 2. Five of 16 patients developed additional brief paroxysmal episodes in puberty, either dystonic/dyskinetic or "shivering" attacks, triggered by stretching, motor initiation, or emotional stimuli. In 1 case, we recorded typical PKD spells by video-EEG-polygraphy, documenting a cortical involvement. INTERPRETATION: Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes.

Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis.

Sarcoidosis is a complex chronic inflammatory disorder with predominant manifestation in the lung. In the first genome-wide association study (> 440,000 SNPs) of this disease, comprising 499 German individuals with sarcoidosis and 490 controls, we detected a series of genetic associations. The strongest association signal maps to the ANXA11 (annexin A11) gene on chromosome 10q22.3. Validation in an independent sample (1,649 cases, 1,832 controls) confirmed the association (SNP rs2789679: P = 3.0 x 10(-13), rs7091565: P = 1.0 x 10(-5), allele-based test). Extensive fine mapping located the association signal to a region between exon 5 and exon 14 of ANXA11. A common nonsynonymous SNP (rs1049550, C > T, [corrected] R230C) was found to be strongly associated with sarcoidosis. The GWAS lead SNP and additional risk variants in the region (rs1953600, rs2573346, rs2784773) were in strong linkage disequilibrium with rs1049550. Annexin A11 has complex and essential functions in several biological pathways, including apoptosis and proliferation.

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Rare variants in γ-aminobutyric acid type A receptor genes in rolandic epilepsy and related syndromes.

OBJECTIVE: To test whether mutations in γ-aminobutyric acid type A receptor (GABAA -R) subunit genes contribute to the etiology of rolandic epilepsy (RE) or its atypical variants (ARE). METHODS: We performed exome sequencing to compare the frequency of variants in 18 GABAA -R genes in 204 European patients with RE/ARE versus 728 platform-matched controls. Identified GABRG2 variants were functionally assessed for protein stability, trafficking, postsynaptic clustering, and receptor function. RESULTS: Of 18 screened GABAA -R genes, we detected an enrichment of rare variants in the GABRG2 gene in RE/ARE patients (5 of 204, 2.45%) in comparison to controls (1 of 723, 0.14%; odds ratio = 18.07, 95% confidence interval = 2.01-855.07, p = 0.0024, pcorr = 0.043). We identified a GABRG2 splice variant (c.549-3T>G) in 2 unrelated patients as well as 3 nonsynonymous variations in this gene (p.G257R, p.R323Q, p.I389V). Functional assessment showed reduced surface expression of p.G257R and decreased GABA-evoked currents for p.R323Q. The p.G257R mutation displayed diminished levels of palmitoylation, a post-translational modification crucial for trafficking of proteins to the cell membrane. Enzymatically raised palmitoylation levels restored the surface expression of the p.G257R variant γ2 subunit. INTERPRETATION: The statistical association and the functional evidence suggest that mutations of the GABRG2 gene may increase the risk of RE/ARE. Restoring the impaired membrane trafficking of some GABRG2 mutations by enhancing palmitoylation might be an interesting therapeutic approach to reverse the pathogenic effect of such mutants.

Continent-wide decoupling of Y-chromosomal genetic variation from language and geography in native South Americans.

Numerous studies of human populations in Europe and Asia have revealed a concordance between their extant genetic structure and the prevailing regional pattern of geography and language. For native South Americans, however, such evidence has been lacking so far. Therefore, we examined the relationship between Y-chromosomal genotype on the one hand, and male geographic origin and linguistic affiliation on the other, in the largest study of South American natives to date in terms of sampled individuals and populations. A total of 1,011 individuals, representing 50 tribal populations from 81 settlements, were genotyped for up to 17 short tandem repeat (STR) markers and 16 single nucleotide polymorphisms (Y-SNPs), the latter resolving phylogenetic lineages Q and C. Virtually no structure became apparent for the extant Y-chromosomal genetic variation of South American males that could sensibly be related to their inter-tribal geographic and linguistic relationships. This continent-wide decoupling is consistent with a rapid peopling of the continent followed by long periods of isolation in small groups. Furthermore, for the first time, we identified a distinct geographical cluster of Y-SNP lineages C-M217 (C3*) in South America. Such haplotypes are virtually absent from North and Central America, but occur at high frequency in Asia. Together with the locally confined Y-STR autocorrelation observed in our study as a whole, the available data therefore suggest a late introduction of C3* into South America no more than 6,000 years ago, perhaps via coastal or trans-Pacific routes. Extensive simulations revealed that the observed lack of haplogroup C3* among extant North and Central American natives is only compatible with low levels of migration between the ancestor populations of C3* carriers and non-carriers. In summary, our data highlight the fact that a pronounced correlation between genetic and geographic/cultural structure can only be expected under very specific conditions, most of which are likely not to have been met by the ancestors of native South Americans.

Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10(-8)) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p(rs1250544) = 3.53 × 10(-8), 11q13 near PRDX5, p(rs694739) = 3.71 × 10(-09), 22q11 at YDJC, p(rs181359) = 8.02 × 10(-10)). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p(rs4780355) = 4.99 × 10(-8)). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.