Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Improving genetic risk modeling of dementia from real-world data in underrepresented populations.

BACKGROUND: Genetic risk modeling for dementia offers significant benefits, but studies based on real-world data, particularly for underrepresented populations, are limited. METHODS: We employed an Elastic Net model for dementia risk prediction using single-nucleotide polymorphisms prioritized by functional genomic data from multiple neurodegenerative disease genome-wide association studies. We compared this model with APOE and polygenic risk score models across genetic ancestry groups, using electronic health records from UCLA Health for discovery and All of Us cohort for validation. RESULTS: Our model significantly outperforms other models across multiple ancestries, improving the area-under-precision-recall curve by 21-61% and the area-under-the-receiver-operating characteristic by 10-21% compared to the APOEand the polygenic risk score models. We identified shared and ancestry-specific risk genes and biological pathways, reinforcing and adding to existing knowledge. CONCLUSIONS: Our study highlights benefits of integrating functional mapping, multiple neurodegenerative diseases, and machine learning for genetic risk models in diverse populations. Our findings hold potential for refining precision medicine strategies in dementia diagnosis.

Improving genetic risk modeling of dementia from real-world data in underrepresented populations.

BACKGROUND: Genetic risk modeling for dementia offers significant benefits, but studies based on real-world data, particularly for underrepresented populations, are limited. METHODS: We employed an Elastic Net model for dementia risk prediction using single-nucleotide polymorphisms prioritized by functional genomic data from multiple neurodegenerative disease genome-wide association studies. We compared this model with APOE and polygenic risk score models across genetic ancestry groups, using electronic health records from UCLA Health for discovery and All of Us cohort for validation. RESULTS: Our model significantly outperforms other models across multiple ancestries, improving the area-under-precision-recall curve by 21-61% and the area-under-the-receiver-operating characteristic by 10-21% compared to the APOE and the polygenic risk score models. We identified shared and ancestry-specific risk genes and biological pathways, reinforcing and adding to existing knowledge. CONCLUSIONS: Our study highlights benefits of integrating functional mapping, multiple neurodegenerative diseases, and machine learning for genetic risk models in diverse populations. Our findings hold potential for refining precision medicine strategies in dementia diagnosis.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Trypanosoma cruzi reservoir-triatomine vector co-occurrence networks reveal meta-community effects by synanthropic mammals on geographic dispersal.

Contemporary patterns of land use and global climate change are modifying regional pools of parasite host species. The impact of host community changes on human disease risk, however, is difficult to assess due to a lack of information about zoonotic parasite host assemblages. We have used a recently developed method to infer parasite-host interactions for Chagas Disease (CD) from vector-host co-occurrence networks. Vector-host networks were constructed to analyze topological characteristics of the network and ecological traits of species' nodes, which could provide information regarding parasite regional dispersal in Mexico. Twenty-eight triatomine species (vectors) and 396 mammal species (potential hosts) were included using a data-mining approach to develop models to infer most-likely interactions. The final network contained 1,576 links which were analyzed to calculate centrality, connectivity, and modularity. The model predicted links of independently registered Trypanosoma cruzi hosts, which correlated with the degree of parasite-vector co-occurrence. Wiring patterns differed according to node location, while edge density was greater in Neotropical as compared to Nearctic regions. Vectors with greatest public health importance (i.e., Triatoma dimidiata, T. barberi, T. pallidipennis, T. longipennis, etc), did not have stronger links with particular host species, although they had a greater frequency of significant links. In contrast, hosts classified as important based on network properties were synanthropic mammals. The latter were the most common parasite hosts and are likely bridge species between these communities, thereby integrating meta-community scenarios beneficial for long-range parasite dispersal. This was particularly true for rodents, >50% of species are synanthropic and more than 20% have been identified as T. cruzi hosts. In addition to predicting potential host species using the co-occurrence networks, they reveal regions with greater expected parasite mobility. The Neotropical region, which includes the Mexican south and southeast, and the Transvolcanic belt, had greatest potential active T. cruzi dispersal, as well as greatest edge density. This information could be directly applied for stratification of transmission risk and to design and analyze human-infected vector contact intervention efficacy.

Cost-Effectiveness of Blood Donation Screening for Trypanosoma cruzi in Mexico.

An estimated 2 million inhabitants are infected with Chagas disease in Mexico, with highest prevalence coinciding with highest demographic density in the southern half of the country. After vector-borne transmission, Trypanosoma cruzi is principally transmitted to humans via blood transfusion. Despite initiation of serological screening of blood donations or donors for T. cruzi since 1990 in most Latin American countries, Mexico only finally included mandatory serological screening nationwide in official Norms in 2012. Most recent regulatory changes and segmented blood services in Mexico may affect compliance of mandatory screening guidelines. The objective of this study was to calculate the incremental cost-effectiveness ratio for total compliance of current guidelines from both Mexican primary healthcare and regular salaried worker health service institutions: the Secretary of Health and the Mexican Institute for Social Security. We developed a bi-modular model to analyze compliance using a decision tree for the most common screening algorithms for each health institution, and a Markov transition model for the natural history of illness and care. The incremental cost effectiveness ratio based on life-years gained is US$ 383 for the Secretary of Health, while the cost for an additional life-year gained is US$ 463 for the Social Security Institute. The results of the present study suggest that due to incomplete compliance of Mexico's national legislation during 2013 and 2014, the MoH has failed to confirm 15,162 T. cruzi infections, has not prevented 2,347 avoidable infections, and has lost 333,483 life-years. Although there is a vast difference in T. cruzi prevalence between Bolivia and Mexico, Bolivia established mandatory blood screening for T.cruzi in 1996 and until 2002 detected and discarded 11,489 T. cruzi -infected blood units and prevented 2,879 potential infections with their transfusion blood screening program. In the first two years of Mexico's mandated program, the two primary institutions failed to prevent due to incomplete compliance more potential infections than those gained from the first five years of Bolivia's program. Full regulatory compliance should be clearly understood as mandatory for the sake of blood security, and its monitoring and analysis in Mexico should be part of the health authority's responsibility.

Cost-effectiveness of implementation methods for ELISA serology testing of Trypanosoma cruzi in California blood banks.

The first U.S. ELISA test for T. cruzi antibodies was licensed by the Food and Drug Administration (FDA) on December 13, 2006. Blood banks have begun screening in absence of FDA recommendations for best implementation methods. We surveyed 2,029 blood donors at five California sites with three risk-based Chagas risk-screening questions. Semi-Markov models compared the cost-effectiveness of three testing strategies. 30% of donors screened positively. Screening all dominated doing nothing, being less costly, and saving more lives. The choice to "screen and test" compared with "testing all" varied by Chagas prevalence, "screening and testing" being cost-effective for high (0.004) and low (0.00004) prevalences, and "testing all" cost-effective for moderate risk (0.0004). It is cost-effective to screen by ELISA rather than do nothing. The best strategy depends on site-specific risk. Census estimates of Hispanics do not predict donor risk well. We suggest using our screening questions to determine risk level and most cost-effective testing strategy.

[Safety of the blood supply in Mexico from 1999 to 2003]. / La seguridad de las reservas sanguíneas en la República Mexicana durante los años 1999 a 2003.

INTRODUCTION: The incidence of the infection by the viruses of the human immunodeficiency (HIV), hepatitis B (HBV) and hepatitis C (HCV) has diminished enormously in developed countries during the last 20 years; nevertheless, in our country we do not know such an incidence and, therefore, the safety of our blood supply. MATERIAL AND METHODS: We performed a retrospective analysis at the Centro Nacional de la Transfusión Sanguínea (CNTS) assessing 17,176,298 serologic tests including HIV, HCV and HBV carried on 5,725,432 blood units collected and informed to the CNTS from January 1999 to December 2003 by all the Mexican blood banks. Prevalence, incidence and residual risk of each one of the aforementioned serologic markers were calculated. RESULTS: The five years mean prevalence for HIV, HBV and HCV has remained steady. The residual risk (RR) when hemagglutination test was employed was 1:977 for HCV; 1:1,564 for HBV and 1:1,262 for HIV. Whereas the RR when ELISA was performed decreased to 1:2,781 for HCV; 1:3,185 for HBV and 1:9,969 for HIV. If nucleic acid amplification test were employed, RR would be 1:8,170 for HBV; 1:9,915 for HCV and 1:19,939 for HIV. CONCLUSIONS: The theoretical risk for transfusion-transmitted diseases in our country is still worrisome.

La seguridad de las reservas sanguíneas en la República Mexicana durante los años 1999 a 2003 / Safety of the blood supply in Mexico from 1999 to 2003

Introduction. The incidence of the infection by the viruses of the human immunodeficiency (HIV), hepatitis B (HBV) and hepatitis C (HCV) has diminished enormously in developed countries during the last 20 years; nevertheless, in our country we do not know such an incidence and, therefore, the safety of our blood supply. Material and methods. We performed a retrospective analysis at the Centro Nacional de la Transfusión Sanguínea (CNTS) assessing 17,176,298 serologic tests including HIV, HCV and HBV carried on 5,725,432 blood units collected and informed to the CNTS from January 1999 to December 2003 by all the Mexican blood banks. Prevalence, incidence and residual risk of each one of the aforementioned serologic markers were calculated. Results. The five years mean prevalence for HIV, HBV and HCV has remained steady. The residual risk (RR) when hemagglutination test was employed was 1:977 for HCV; 1:1,564 for HBV and 1:1,262 for HIV. Whereas the RR when ELISA was performed decreased to 1:2,781 for HCV; 1:3,185 for HBV and 1:9,969 for HIV. If nucleic acid amplification test were employed, RR would be 1:8,170 for HBV; 1:9,915 for HCV and 1:19,939 for HIV. Conclusions. The theoretical risk for transfusion-transmitted diseases in our country is still worrisome.

Introducción. La transmisión del virus de la inmunodeficiencia humana (VIH), de la hepatitis C (VHC) y de la hepatitis B (VHB) por transfusión sanguínea ha disminuido de manera significativa en los países industrializados durante los últimos 20 años; sin embargo, en nuestro país aún no conocemos dicha incidencia y consecuentemente la seguridad de nuestras reservas sanguíneas. Material y métodos. Se realizó un estudio retrospectivo en el Centro Nacional de la Transfusión Sanguínea (CNTS) analizando 17,176,298 pruebas serológicas incluyendo VIH, VHC y VHB realizadas a 5,725,432 unidades de sangre captadas e informadas al CNTS de enero de 1999 a diciembre de 2003 por todos los bancos de la República Mexicana. Se calcularon la prevalencia, la incidencia y el riesgo residual para cada uno de los marcadores serológicos mencionados. Resultados. La prevalencia en los cinco años para el VIH, VHB y VHC se ha mantenido estable entre los donantes. El riesgo residual encontrado con la prueba de hemaglutinación fue de 1:977 para el VHC; de 1:1,564 para el VHB y de 1:1,262 para el VIH. Con la prueba de ELISA el riesgo descendió a 1:2,781 para el VHC; 1:3,185 para el VHB y 1:9,969 para el VIH. Si se empleara la prueba de amplificación de ácidos nucleicos, el riesgo disminuiría a 1:8,170 para el VHB; 1:9,915 para el VHC y a 1:19,939 para el VIH. Conclusiones. El riesgo de transmitir infecciones por transfusión sanguínea en nuestro país es todavía preocupante.

Detection of West Nile virus in the Mexican blood supply.

BACKGROUND: West Nile virus (WNV) is the etiologic agent of an emerging disease in the Western Hemisphere that can be transmitted to humans by blood transfusion. WNV first appeared in the United States in 1999, in Canada in 2001, and in Mexico in 2002. The aim of this nationwide study was to determine the prevalence of WNV in blood donors in Mexico as a first step in preventing its transfusion-associated transmission. STUDY DESIGN AND METHODS: In July and August 2004, a total of 3856 fresh plasma specimens collected from each state's center for blood transfusion in 29 of 31 Mexican states were screened with an investigational WNV assay (Procleix,(R) Gen-Probe Inc. and Chiron Corp.), a nucleic acid test based on transcription-mediated amplification (TMA). Reactive specimens were confirmed with a second TMA-based test, the alternative WNV assay (Gen-Probe), and with WNV capture enzyme-linked immunosorbent assays (ELISAs) for detection of immunoglobulin M (IgM) and IgG antibodies. In addition, 3714 frozen plasma samples collected in 2002 and 2003 were similarly tested. RESULTS: One of 3856 fresh samples from an asymptomatic donor from Chihuahua was reactive by both TMA-based tests and IgM ELISA, suggesting a recently acquired infection. The observed percentage of viremic donors blood donors was 0.03 percent. Results from frozen samples were not included in the prevalence calculation and none were TMA-reactive for WNV. CONCLUSIONS: WNV is present in the Mexican blood supply and measures should be taken to reduce the risk of transfusion transmission.