Biomedical subjects

John Farrell

Publications and source records attributed to John Farrell.

12 recordsLinked to original sources

PubMed2026

A multiancestry polygenic risk score for Alzheimer's disease is associated with cognitive decline and neuropathological hallmarks in diverse populations.

Previously derived polygenic risk scores (PRSs) for Alzheimer's disease (AD) perform inconsistently across diverse ancestries. We developed an APOE-independent multiancestry AD PRS using genome-wide association study summary statistics applied to European ancestry, African American, Caribbean Hispanic and East Asian cohorts. PRS performance was evaluated in a large independent multiancestry dataset and validated in several additional multiancestry cohorts. The PRS was significantly associated with AD in European ancestry, African American, Caribbean Hispanic and Native American Hispanic groups with adjusted odds ratios between 1.14 and 1.52 per PRS standard deviation. PRS performance was validated in the replication cohorts (odds ratios: 1.21-1.65). The PRS was also associated with poorer memory, executive function and language performance, greater AD-related neuropathological burden, reduced hippocampal volume, lower cerebrospinal fluid amyloid-β42 and elevated total tau and phosphorylated tau, with stronger phosphorylated tau associations observed in women. Our findings support the value of ancestry-aware PRSs as a component of broader multimodal risk stratification frameworks.

Aged↗

PubMed2025

A multi-ancestry polygenic risk score for Alzheimer disease is associated with cognitive decline, hippocampal atrophy and neuropathological hallmarks in diverse populations.

Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.

Journal Article↗

PubMed2005

Multifactor-dimensionality reduction versus family-based association tests in detecting susceptibility loci in discordant sib-pair studies.

Complex diseases are generally thought to be under the influence of multiple, and possibly interacting, genes. Many association methods have been developed to identify susceptibility genes assuming a single-gene disease model, referred to as single-locus methods. Multilocus methods consider joint effects of multiple genes and environmental factors. One commonly used method for family-based association analysis is implemented in FBAT. The multifactor-dimensionality reduction method (MDR) is a multilocus method, which identifies multiple genetic loci associated with the occurrence of complex disease. Many studies of late onset complex diseases employ a discordant sib pairs design. We compared the FBAT and MDR in their ability to detect susceptibility loci using a discordant sib-pair dataset generated from the simulated data made available to participants in the Genetic Analysis Workshop 14. Using FBAT, we were able to identify the effect of one susceptibility locus. However, the finding was not statistically significant. We were not able to detect any of the interactions using this method. This is probably because the FBAT test is designed to find loci with major effects, not interactions. Using MDR, the best result we obtained identified two interactions. However, neither of these reached a level of statistical significance. This is mainly due to the heterogeneity of the disease trait and noise in the data.

Chromosome Mapping↗

PubMed2005

Whole-genome variance components linkage analysis using single-nucleotide polymorphisms versus microsatellites on quantitative traits of derived phenotypes from factor analysis of electroencephalogram waves.

Alcohol dependence is a serious public health problem. We studied data from families participating in the Collaborative Study on the Genetics of Alcoholism (COGA) and made available to participants in the Genetic Analysis Workshop 14 (GAW14) in order to search for genes predisposing to alcohol dependence. Using factor analysis, we identified four factors (F1, F2, F3, F4) related to the electroencephalogram traits. We conducted variance components linkage analysis with each of the factors. Our results using the Affymetrix single-nucleotide polymorphism dataset showed significant evidence for a novel linkage of F3 (factor comprised of the three midline channel EEG measures from the target case of the Visual Oddball experiment ttdt2, 3, 4) to chromosome 18 (LOD = 3.45). This finding was confirmed by analyses of the microsatellite data (LOD = 2.73) and Illumina SNP data (LOD = 3.30). We also demonstrated that, in a sample like the COGA data, a dense single-nucleotide polymorphism map provides better linkage signals than low-resolution microsatellite map with quantitative traits.

Chromosome Mapping↗

PubMed2005

Genome-wide linkage analysis for alcohol dependence: a comparison between single-nucleotide polymorphism and microsatellite marker assays.

Both theoretical and applied studies have proven that the utility of single nucleotide polymorphism (SNP) markers in linkage analysis is more powerful and cost-effective than current microsatellite marker assays. Here we performed a whole-genome scan on 115 White, non-Hispanic families segregating for alcohol dependence, using one 10.3-cM microsatellite marker set and two SNP data sets (0.33-cM, 0.78-cM spacing). Two definitions of alcohol dependence (ALDX1 and ALDX2) were used. Our multipoint nonparametric linkage analysis found alcoholism was nominal linked to 12 genomic regions. The linkage peaks obtained by using the microsatellite marker set and the two SNP sets had a high degree of correspondence in general, but the microsatellite marker set was insufficient to detect some nominal linkage peaks. The presence of linkage disequilibrium between markers did not significantly affect the results. Across the entire genome, SNP datasets had a much higher average linkage information content (0.33 cM: 0.93, 0.78 cM: 0.91) than did microsatellite marker set (0.57). The linkage peaks obtained through two SNP datasets were very similar with some minor differences. We conclude that genome-wide linkage analysis by using approximately 5,000 SNP markers evenly distributed across the human genome is sufficient and might be more powerful than current 10-cM microsatellite marker assays.

Alcoholism↗

PubMed2005

Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis.

In patients with sickle cell disease, clinical complications including osteonecrosis can vary in frequency and severity, presumably due to the effects of genes that modify the pathophysiology initiated by the sickle mutation. Here, we examined the association of single nucleotide polymorphisms (SNPs) in candidate genes (cytokines, inflammation, oxidant stress, bone metabolism) with osteonecrosis in patients with sickle cell disease. Genotype distributions were compared between cases and controls using multiple logistic regression techniques. An initial screen and follow-up studies showed that individual SNPs and haplotypes composed of several SNPs in bone morphogenic protein 6, annexin A2, and klotho were associated with sickle cell osteonecrosis. These genes are important in bone morphology, metabolism, and vascular disease. Our results may provide insight into the pathogenesis of osteonecrosis in sickle cell disease, help identify individuals who are at high risk for osteonecrosis, and thus allow earlier and more effective therapeutic intervention.

Anemia, Sickle Cell↗

PubMed2005

Characterization of the T-cell response in a patient with phenindione hypersensitivity.

The oral anticoagulant phenindione [2-phenyl-1H-indene-1,3(2H)-dione] is associated with hypersensitivity reactions in 1.5 to 3% of patients, the pathogenesis of which is unclear. We describe a patient who developed a severe hypersensitivity reaction that involved both the skin and lungs. A lymphocyte transformation test showed proliferation of T-cells from the hypersensitive patient, but not from four controls on exposure to phenindione in vitro. Drug-specific T-cell clones were generated and characterized in terms of their phenotype, functionality, and mechanism of antigen presentation. Forty-three human leukocyte antigen class II restricted CD4(+) alphabeta T-cell clones were identified. T-cell activation resulted in the secretion of interferon-gamma and interleukin-5. Five of seven clones proliferated with phenindione alone, whereas two clones also proliferated with 2-phenylindene. Certain T-cell clones were also stimulated by R- and S-warfarin; computer modeling revealed that warfarin can adopt a phenindione-like structure. Phenindione was presented to T-cells via two pathways: first, bound directly to major histocompatibility complex and second, bound to a processed peptide. Our data show that CD4(+) T-cells are involved in the pathophysiology of phenindione hypersensitivity. There may be cross-sensitivity with warfarin in some phenindione hypersensitive patients.

Drug Hypersensitivity↗

PubMed2003

Search for genetic factors predisposing to atherogenic dyslipidemia.

BACKGROUND: Atherogenic dyslipidemia (AD) is a common feature in persons with premature coronary heart disease. While several linkage studies have been carried out to dissect the genetic etiology of lipid levels, few have investigated the AD lipid triad comprising elevated serum triglyceride, small low density lipoprotein (LDL) particles, and reduced high density lipoprotein (HDL) cholesterol levels. Here we report the results of a whole-genome screen for AD using the Framingham Heart Study population. RESULTS: Our analyses provide some evidence for linkage to AD on chromosomes 1q31, 3q29, 10q26, 14p12, 14q13, 16q24, 18p11, and 19q13. CONCLUSION: AD susceptibility is modulated by multiple genes in different chromosomes. Our study confirms results from other populations and suggests new areas of potential importance.

Adult Children↗

PubMed2003

Empirically derived phenotypic subgroups - qualitative and quantitative trait analyses.

BACKGROUND: The Framingham Heart Study has contributed a great deal to advances in medicine. Most of the phenotypes investigated have been univariate traits (quantitative or qualitative). The aims of this study are to derive multivariate traits by identifying homogeneous groups of people and assigning both qualitative and quantitative trait scores; to assess the heritability of the derived traits; and to conduct both qualitative and quantitative linkage analysis on one of the heritable traits. METHODS: Multiple correspondence analysis, a nonparametric analogue of principal components analysis, was used for data reduction. Two-stage clustering, using both k-means and agglomerative hierarchical clustering, was used to cluster individuals based upon axes (factor) scores obtained from the data reduction. Probability of cluster membership was calculated using binary logistic regression. Heritability was calculated using SOLAR, which was also used for the quantitative trait analysis. GENEHUNTER-PLUS was used for the qualitative trait analysis. RESULTS: We found four phenotypically distinct groups. Membership in the smallest group was heritable (38%, p < 1 x 10(-6)) and had characteristics consistent with atherogenic dyslipidemia. We found both qualitative and quantitative LOD scores above 3 on chromosomes 11 and 14 (11q13, 14q23, 14q31). There were two Kong & Cox LOD scores above 1.0 on chromosome 6 (6p21) and chromosome 11 (11q23). CONCLUSION: This approach may be useful for the identification of genetic heterogeneity in complex phenotypes by clarifying the phenotype definition prior to linkage analysis. Some of our findings are in regions linked to elements of atherogenic dyslipidemia and related diagnoses, some may be novel, or may be false positives.

Adult Children↗

PubMed2003

Characterization of sulfamethoxazole and sulfamethoxazole metabolite-specific T-cell responses in animals and humans.

Sulfamethoxazole (SMX) is associated with hypersensitivity reactions. Identification of drug-specific lymphocytes from hypersensitive patients suggests involvement of the immune system. Lymphocytes from humans recognize SMX and nitroso-SMX (SMX-NO), whereas cells from sensitized rats recognize only SMX-NO. In this investigation, we study the nature of SMX-specific T cells in four species. Male rats, mice, and rabbits were immunized with SMX (50 mg kg-1) or SMX-NO (1 mg kg-1). Lymphocytes and/or splenocytes were isolated and incubated with SMX, SMX-hydroxylamine or SMX-NO and proliferation were measured. Lymphocytes were also isolated from SMX-hypersensitive patients (n = 3) and drug-specific proliferation was measured. In addition, rabbits were bled fortnightly for 4 months to determine whether SMX-NO-specific T cells cross-react with SMX. To confirm that SMX-NO responses were due to covalent binding and not cross-reactivity, cells were pulsed with SMX-NO and/or coincubated with glutathione. Splenocytes from mice, rats, and rabbits proliferated when stimulated with SMX-NO, but not SMX. A 2-h pulse with SMX-NO was sufficient for proliferation, whereas cells coincubated with SMX-NO and glutathione did not proliferate. Rabbit lymphocytes proliferated in the presence of SMX-NO and SMX-hydroxylamine, but not SMX. SMX-hydroxylamine was converted to SMX-NO in culture. The SMXNO-specific response of rabbit lymphocytes was maintained for at least 4 months and the cells did not cross-react with SMX. Human lymphocytes from hypersensitive patients proliferated in the presence of SMX and both metabolites. These results highlight important differences in T-cell recognition of drug (metabolite) antigens in animals that have been sensitized against a drug metabolite and patients with hypersensitivity to the drug.

Animals↗

PubMed2003

Characterization of drug-specific T cells in lamotrigine hypersensitivity.

BACKGROUND: Lamotrigine is associated with hypersensitivity reactions, which are most commonly characterized by skin rash. An immune etiology has been postulated, though the nature of this is unclear. OBJECTIVES: The aim of this study was to characterize the role of T cells in lamotrigine hypersensitivity. METHODS: A lymphocyte transformation test was performed on 4 hypersensitive patients. Lymphocytes from 3 of 4 lamotrigine-hypersensitive patients proliferated when stimulated with lamotrigine. T-cell clones were generated from one patient to further characterize the nature of the T-cell involvement. Cells were characterized in terms of their phenotype, functionality, and mechanisms of antigen presentation and cytotoxicity. RESULTS: Of the 44 drug-specific T-cell clones generated, most were CD4(+) with occasional CD8(+) cells. All clones expressed the alphabeta T-cell receptor; several Vbeta 5.1(+) or 9(+) T-cell clones were generated. All clones also expressed the skin-homing receptor cutaneous lymphocyte antigen. Lamotrigine-stimulated T cells were cytotoxic and secreted perforin, IFN-gamma, IL-5, and macrophage inflammatory protein 1alpha, macrophage inflammatory protein 1beta, RANTES, and I-309. Lamotrigine was present on HLA-DR and HLA-DQ by antigen-presenting cells in the absence of drug metabolism and processing. The T-cell receptor of certain clones could accommodate analogs of lamotrigine, but no cross-reactivity was seen with other anticonvulsants. CONCLUSIONS: Our data provide evidence that T cells are involved in the pathogenesis of some lamotrigine-hypersensitivity reactions. The identification of drug-specific cells that express cutaneous lymphocyte antigen and type 1 cytokines after T-cell receptor activation is consistent with the clinical symptoms. Furthermore, identification of large numbers of Vbeta 5.1(+) T cells suggests that polymorphisms within T-cell receptor genes might act as determinants of susceptibility.

Adult↗

PubMed2002

Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation.

Treatment with sulfamethoxazole (SMX) can lead to hypersensitivity reactions. T cells from hypersensitive patients recognize either the parent drug and/or the reactive nitroso (SMX-NO) metabolite. In this study, using a novel in vitro rat splenocyte assay, we have investigated the toxicological and immunological consequences of cell surface haptenation by SMX-NO. SMX-NO was found to be unstable in solution; spontaneous transformation yielded appreciable amounts of SMX-hydroxylamine, nitro-SMX, and the previously unknown azoxy and azo dimers within 15 min. Irreversible binding of SMX-NO to cellular protein was demonstrated by flow cytometry, with haptenation being greater on the surface of antigen-presenting cells than on T cells. The consequences of irreversible binding of SMX-NO were examined in two ways. First, haptenation above a threshold level led to a proportionate increase in cell death (both apoptosis and necrosis). Indeed, the cells that became haptenated were the same as those that underwent necrotic cell death. Second, sensitized splenocytes proliferated in the presence of major histocompatibility complex (MHC)-restricted antigen derived from both viable and dead cells haptenated with low and high levels of SMX-NO, respectively. However, direct modification of MHC by SMX-NO was not the mechanism of antigen presentation. The antigenic threshold of SMX-NO for T-cell proliferation and toxicity was estimated to be between 0.5 and 1 microM and 5 to 10 microM, respectively. The potential of SMX-NO to generate a potent antigen and cause cytotoxicity may in combination provide the signals necessary to induce a hypersensitivity reaction to SMX.

Animals↗