Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder wellknown for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10 −8 , rs1990620 G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.
Late-Onset Alzheimer’s disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) analysis to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10−8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.
Genetics play an important role in the development of metabolic diseases. However, the relative influence of genetic variation on metabolism is not well defined, particularly in tissues, where metabolic dysfunction that leads to disease occurs. We used inbred strains of laboratory mice to evaluate the impact of genetic variation on the metabolomes of tissues that play central roles in metabolic diseases. We chose a set of four common inbred strains that have different levels of susceptibility to obesity, insulin resistance, and other common metabolic disorders. At the ages used, and under standard husbandry conditions, these lines are not overtly diseased. Using global metabolomics profiling, we evaluated water-soluble metabolites in liver, skeletal muscle, and adipose from A/J, C57BL/6J, FVB/NJ, and NOD/ShiLtJ mice fed a standard mouse chow diet. We included both males and females to assess the relative influence of strain, sex, and strain-by-sex interactions on metabolomes. The mice were also phenotyped for systems level traits related to metabolism and energy expenditure. Strain explained more variation in the metabolite profile than did sex or its interaction with strain across each of the tissues, especially in liver. Purine and pyrimidine metabolism and pathways related to amino acid metabolism were identified as pathways that discriminated strains across all three tissues. Based on the results from ANOVA, sex and sex-by-strain interaction had modest influence on metabolomes relative to strain, suggesting that the tissue metabolome remains largely stable across sexes consuming the same diet. Our data indicate that genetic variation exerts a fundamental influence on tissue metabolism.
Clinic, Rochester, MN, 4 Reading hospital-Tower Health System, West Reading, PA, 5 Division of Pediatric and Adult Allergy / Immunology, Mayo Clinic, Rochester, MN. RATIONALE: IVIG (Intravenous Immunoglobulin) and SCIG (Subcutaneous Immunoglobulin) have been regarded as therapeutically equivalent treatments for primary immunodeficiency diseases (PIDDs). IgG trough level is used as a monitoring measure for infection prevention. A systematic review and meta-analysis was performed in patients with PIDD and relationship between IgG dosing, trough IgG levels with overall infection incidence were evaluated. METHODS: Medline, EMBASE, Cochrane, Central and Scopus were searched for studies published from Jan 2000-June 2018, fulfilling the inclusion criteria. DerSimonian and Laird random-effect method was used to pool difference of IgG trough levels. Random-effect meta-regression was used to evaluate infection incidence per 100 mg/dl IgG trough increase through IVIG and SCIG. RESULTS: Out of 24 observational studies included (1,426 patients), 11 compared IgG trough levels among SCIG and IVIG (mean difference: 73.4 mg/dl, 95% CI: 31.67-119.19 mg/dl, I 2 5 45%, p50.05), favoring SCIG. For every 100 mg/dl increase in trough, a linear trend of decreased incidence rates of infection was identified in SCIG patients (p50.03), but no similar trend was identified in trough levels vs. infection rates for patients receiving IVIG (p50.67). CONCLUSIONS: SCIG is associated with a higher IgG trough level in comparison to IVIG. Higher SCIG troughs were associated with lower infection rates, while IVIG troughs demonstrated no relationship. Abstracts AB205 SUNDAY
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