Citations

Background: Although donor and recipient characteristics are used to estimate graft failure risk, they remain limited in predicting early acute rejection. We developed and validated a next-generation sequencing (NGS) assay targeting the pre-transplant immunologic profile to predict early acute rejection following kidney transplantation. Methods: This prospective, international study enrolled 321 kidney transplant participants across 13 sites, forming discovery and validation cohorts. Peripheral blood was collected prior to transplant and at 1, 3, 6, 12, and 24 months post-transplant, with protocol biopsies performed at 3 and 12 months, as well as any indication biopsies. Biopsies were assessed by a blinded central pathologist according to the 2019 Banff criteria. The pre-transplant risk assessment (PTRA™) test to evaluate RNA expression of a 29-gene signature algorithm designed to predict early acute rejection risk was clinically validated utilizing 122 deceased donor kidney transplant recipients. Results: PTRA classified 31 of 122 participants (25%) as high-risk and 91 (75%) as low-risk. There were 9 early acute rejection events in the first 60 days post-transplant: 6/31 (19%) in the high-risk group and 3/91 (3%) in the low-risk group. PTRA discrimination for early acute rejection at 60 days post-transplant yielded an AUC of 0.78 (95% confidence interval [CI]: 64.4 to 91.5), p<0.001. A cut-off of ≤45 was defined as low-risk and >45 as high-risk for early acute rejection within 60 days post-transplant. Sensitivity 0.67 (95% CI: 0.36 to 0.97), specificity 0.78 (95% CI: 0.70 to 0.86), positive predictive value 0.19 (95% CI: 0.05 to 0.33), and negative predictive value 0.97 (95% CI: 0.93 to 1.00). The odds ratio comparing patients identified as high- vs low-risk by PTRA was 7.04 (95% CI: 1.64 to 30.2), p=0.009. Conclusions: This study validates the ability of PTRA to stratify kidney transplant recipients as high- or low-risk for early acute rejection using a pre-transplant transcriptomic profile, with implications for graft health and personalized treatment management.

ABSTRACT Bipolar disorder’s (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder—and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic–GABAergic gradient along the psychotic factor. BD’s genetic architecture appears hierarchical—a general liability resolving into dimensions of course and comorbidity beyond diagnostic subtypes.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.