Browsing by Subject "ALSPAC"

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    An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs
    (Elsevier, 2021) Cordell, Heather J.; Fryett, James J.; Ueno, Kazuko; Darlay, Rebecca; Aiba, Yoshihiro; Hitomi, Yuki; Kawashima, Minae; Nishida, Nao; Khor, Seik-Soon; Gervais, Olivier; Kawai, Yosuke; Nagasaki, Masao; Tokunaga, Katsushi; Tang, Ruqi; Shi, Yongyong; Li, Zhiqiang; Juran, Brian D.; Atkinson, Elizabeth J.; Gerussi, Alessio; Carbone, Marco; Asselta, Rosanna; Cheung, Angela; de Andrade, Mariza; Baras, Aris; Horowitz, Julie; Ferreira, Manuel A. R.; Sun, Dylan; Jones, David E.; Flack, Steven; Spicer, Ann; Mulcahy, Victoria L.; Byan, Jinyoung; Han, Younghun; Sandford, Richard N.; Lazaridis, Konstantinos N.; Amos, Christopher I.; Hirschfield, Gideon M.; Seldin, Michael F.; Invernizzi, Pietro; Siminovitch, Katherine A.; Ma, Xiong; Nakamura, Minoru; Mells, George F.; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium; Medicine, School of Medicine
    Backgrounds & aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. Lay summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.
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    The Intersection of the Genetic Architectures of Orofacial Clefts and Normal Facial Variation
    (Frontiers Media, 2021-02-22) Indencleef, Karlijne; Hoskens, Hanne; Lee, Myoung Keun; White, Julie D.; Liu, Chenxing; Eller, Ryan J.; Naqvi, Sahin; Wehby, George L.; Moreno Uribe, Lina M.; Hecht, Jacqueline T.; Long, Ross E., Jr.; Christensen, Kaare; Deleyiannis, Frederic W.; Walsh, Susan; Shriver, Mark D.; Richmond, Stephen; Wysocka, Joanna; Peeters, Hilde; Shaffer, John R.; Marazita, Mary L.; Hens, Greet; Weinberg, Seth M.; Claes, Peter; Biology, School of Science
    Unaffected relatives of individuals with non-syndromic cleft lip with or without cleft palate (NSCL/P) show distinctive facial features. The presence of this facial endophenotype is potentially an expression of underlying genetic susceptibility to NSCL/P in the larger unselected population. To explore this hypothesis, we first partitioned the face into 63 partially overlapping regions representing global-to-local facial morphology and then defined endophenotypic traits by contrasting the 3D facial images from 264 unaffected parents of individuals with NSCL/P versus 3,171 controls. We observed distinct facial features between parents and controls across 59 global-to-local facial segments at nominal significance (p ≤ 0.05) and 52 segments at Bonferroni corrected significance (p < 1.2 × 10–3), respectively. Next, we quantified these distinct facial features as univariate traits in another dataset of 8,246 unaffected European individuals and performed a genome-wide association study. We identified 29 independent genetic loci that were associated (p < 5 × 10–8) with at least one of the tested endophenotypic traits, and nine genetic loci also passed the study-wide threshold (p < 8.47 × 10–10). Of the 29 loci, 22 were in proximity of loci previously associated with normal facial variation, 18 were near genes that show strong evidence in orofacial clefting (OFC), and another 10 showed some evidence in OFC. Additionally, polygenic risk scores for NSCL/P showed associations with the endophenotypic traits. This study thus supports the hypothesis of a shared genetic architecture of normal facial development and OFC.