Showing papers by "Matthew Patrick published in 2023"

Multi-ancestry and multi-trait genome-wide association meta-analyses inform clinical risk prediction for systemic lupus erythematosus

Abstract: Abstract Systemic lupus erythematosus is a heritable autoimmune disease that predominantly affects young women. To improve our understanding of genetic etiology, we conduct multi-ancestry and multi-trait meta-analysis of genome-wide association studies, encompassing 12 systemic lupus erythematosus cohorts from 3 different ancestries and 10 genetically correlated autoimmune diseases, and identify 16 novel loci. We also perform transcriptome-wide association studies, computational drug repurposing analysis, and cell type enrichment analysis. We discover putative drug classes, including a histone deacetylase inhibitor that could be repurposed to treat lupus. We also identify multiple cell types enriched with putative target genes, such as non-classical monocytes and B cells, which may be targeted for future therapeutics. Using this newly assembled result, we further construct polygenic risk score models and demonstrate that integrating polygenic risk score with clinical lab biomarkers improves the diagnostic accuracy of systemic lupus erythematosus using the Vanderbilt BioVU and Michigan Genomics Initiative biobanks.

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis

Abstract: Significance Statement Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA–DRβ1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. Background Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. Methods We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. Results Two genome-wide significant loci, rs35087390 of HLA-DQA1 (P=3.01×10−39) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 (P=2.14×10−8), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association. HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. Conclusions We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.

Shared Genetic Risk Factors for MS/Psoriasis suggest involvement of IL17 and JAK-STAT signaling.

Abstract: OBJECTIVE Psoriasis and multiple sclerosis (MS) are complex immune diseases that are mediated by T-cells and share multiple comorbidities. Previous studies have suggested psoriatic patients are at higher risk of MS; however, causal relationships between the two conditions remain unclear. Through epidemiology and genetics, we provide a comprehensive understanding of the relationship and shared molecular factors between psoriasis and MS. METHODS We used logistic regression, trans-disease meta-analysis (TDMA) and Mendelian randomization (MR). Medical claims data was included from 30 million patients, including 141,544 with MS and 742,919 with psoriasis. We used GWAS summary statistics from 11,024 psoriatic, 14,802 MS cases and 43,039 controls for TDMA, with additional summary statistics from 5 million individuals for MR. RESULTS Psoriatic patients have significantly higher risk of MS (4,637 patients with both diseases; OR=1.07, p=1.2×10-5 ), after controlling for potential confounders. Using inverse variance and equally weighted TDMA, we revealed more than 20 shared and opposing (direction of effect) genetic loci outside the MHC which show significant genetic colocalization (in COLOC and COLOC-SuSiE v5.1.0). Co-expression analysis of genes from these loci further identified distinct clusters which were enriched among pathways for IL-17/TNFα (p<1.6×10-3 , OR>39) and JAK-STAT (p=1.1×10-5 , OR=35), including genes such as TNFAIP3, TYK2 and TNFRSF1A. MR found psoriasis as an exposure has a significant causal effect on MS (OR=1.04, p=5.8×10-3 ), independent of T1D (p=4.3×10-7 , OR=1.05), T2D (p=2.3×10-3 , OR=1.08), IBD (p=1.6×10-11 , OR=1.11) and vitamin D level (p=9.4×10-3 , OR=0.75). INTERPRETATION By investigating the shared genetics of psoriasis and MS, along with their modifiable risk factors, our findings will advance innovations in treatment for patients suffering from comorbidities. This article is protected by copyright. All rights reserved.