Evaluation of gene-based family-based methods to detect novel genes associated with familial late onset Alzheimer disease

AbstractGene-based tests to study the combined effect of rare variants towards a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially for complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We have examined the performance of several collapsing, variance-component and transmission disequilibrium tests across eight different software and twenty-two models utilizing a cohort of 285 families (N=1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the studied phenotype with high confidence and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, MAS1L) as candidates genes for familial LOAD.</jats:p

Genome-wide survival analysis of age at onset of alcohol dependence in extended high-risk COGA families.

BackgroundThe age at onset of alcohol dependence (AD) is a critical moderator of genetic associations for alcohol dependence. The present study evaluated whether single nucleotide polymorphisms (SNPs) can influence the age at onset of AD in large high-risk families from the Collaborative Study on the Genetics of Alcoholism (COGA).MethodsGenomewide SNP genotyping was performed in 1788 regular drinkers from 118 large European American families densely affected with alcoholism. We used a genome-wide Cox proportional hazards regression model to test for association between age at onset of AD and SNPs.ResultsThis family-based analysis identified an intergenic SNP, rs2168784 on chromosome 3 that showed strong evidence of association (P=5×10(-9)) with age at onset of AD among regular drinkers. Carriers of the minor allele of rs2168784 had 1.5 times the hazard of AD onset as compared with those homozygous for the major allele. By the age of 20 years, nearly 30% of subjects homozygous for the minor allele were alcohol dependent while only 19% of those homozygous for the major allele were. We also identified intronic SNPs in the ADP-ribosylation factor like 15 (ARL15) gene on chromosome 5 (P=1.11×10(-8)) and the UTP20 small subunit (UTP20) gene on chromosome 12 (P=4.32×10(-8)) that were associated with age at onset of AD.ConclusionsThis extended family based genome-wide cox-proportional hazards analysis identified several loci that might be associated with age at onset of AD

Rare missense variants in CHRNB3 and CHRNA3 are associated with risk of alcohol and cocaine dependence

Previous findings have demonstrated that variants in nicotinic receptor genes are associated with nicotine, alcohol and cocaine dependence. Because of the substantial comorbidity, it has often been unclear whether a variant is associated with multiple substances or whether the association is actually with a single substance. To investigate the possible contribution of rare variants to the development of substance dependencies other than nicotine dependence, specifically alcohol and cocaine dependence, we undertook pooled sequencing of the coding regions and flanking sequence of CHRNA5, CHRNA3, CHRNB4, CHRNA6 and CHRNB3 in 287 African American and 1028 European American individuals from the Collaborative Study of the Genetics of Alcoholism (COGA). All members of families for whom any individual was sequenced (2504 African Americans and 7318 European Americans) were then genotyped for all variants identified by sequencing. For each gene, we then tested for association using FamSKAT. For European Americans, we find increased DSM-IV cocaine dependence symptoms (FamSKAT P = 2 × 10−4) and increased DSM-IV alcohol dependence symptoms (FamSKAT P = 5 × 10−4) among carriers of missense variants in CHRNB3. Additionally, one variant (rs149775276H329Y) shows association with both cocaine dependence symptoms (P = 7.4 × 10−5, β = 2.04) and alcohol dependence symptoms (P = 2.6 × 10−4, β = 2.04). For African Americans, we find decreased cocaine dependence symptoms among carriers of missense variants in CHRNA3 (FamSKAT P = 0.005). Replication in an independent sample supports the role of rare variants in CHRNB3 and alcohol dependence (P = 0.006). These are the first results to implicate rare variants in CHRNB3 or CHRNA3 in risk for alcohol dependence or cocaine dependence

Optimization of growth media components for polyhydroxyalkanoate (PHA) production from organic acids by Ralstonia eutropha.

We employed systematic mixture analysis to determine optimal levels of acetate, propionate, and butyrate for cell growth and polyhydroxyalkanoate (PHA) production by Ralstonia eutropha H16. Butyrate was the preferred acid for robust cell growth and high PHA production. The 3-hydroxyvalerate content in the resulting PHA depended on the proportion of propionate initially present in the growth medium. The proportion of acetate dramatically affected the final pH of the growth medium. A model was constructed using our data that predicts the effects of these acids, individually and in combination, on cell dry weight (CDW), PHA content (%CDW), PHA production, 3HV in the polymer, and final culture pH. Cell growth and PHA production improved approximately 1.5-fold over initial conditions when the proportion of butyrate was increased. Optimization of the phosphate buffer content in medium containing higher amounts of butyrate improved cell growth and PHA production more than 4-fold. The validated organic acid mixture analysis model can be used to optimize R. eutropha culture conditions, in order to meet targets for PHA production and/or polymer HV content. By modifying the growth medium made from treated industrial waste, such as palm oil mill effluent, more PHA can be produced

An atlas of cortical circular RNA expression in Alzheimer disease brains demonstrates clinical and pathological associations.

Parietal cortex RNA-sequencing (RNA-seq) data were generated from individuals with and without Alzheimer disease (AD; ncontrol = 13; nAD = 83) from the Knight Alzheimer Disease Research Center (Knight ADRC). Using this and an independent (Mount Sinai Brain Bank (MSBB)) AD RNA-seq dataset, cortical circular RNA (circRNA) expression was quantified in the context of AD. Significant associations were identified between circRNA expression and AD diagnosis, clinical dementia severity and neuropathological severity. It was demonstrated that most circRNA-AD associations are independent of changes in cognate linear messenger RNA expression or estimated brain cell-type proportions. Evidence was provided for circRNA expression changes occurring early in presymptomatic AD and in autosomal dominant AD. It was also observed that AD-associated circRNAs co-expressed with known AD genes. Finally, potential microRNA-binding sites were identified in AD-associated circRNAs for miRNAs predicted to target AD genes. Together, these results highlight the importance of analyzing non-linear RNAs and support future studies exploring the potential roles of circRNAs in AD pathogenesis

Numerical simulation and experimental validation of the cladding material distribution of hybrid semi-finished products produced by deposition welding and cross-wedge rolling

The service life of rolling contacts is dependent on many factors. The choice of materials in particular has a major influence on when, for example, a ball bearing may fail. Within an exemplary process chain for the production of hybrid high-performance components through tailored forming, hybrid solid components made of at least two different steel alloys are investigated. The aim is to create parts that have improved properties compared to monolithic parts of the same geometry. In order to achieve this, several materials are joined prior to a forming operation. In this work, hybrid shafts created by either plasma (PTA) or laser metal deposition (LMD-W) welding are formed via cross-wedge rolling (CWR) to investigate the resulting thickness of the material deposited in the area of the bearing seat. Additionally, finite element analysis (FEA) simulations of the CWR process are compared with experimental CWR results to validate the coating thickness estimation done via simulation. This allows for more accurate predictions of the cladding material geometry after CWR, and the desired welding seam geometry can be selected by calculating the cladding thickness via CWR simulation. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Harinosidad en durazno: Diferencias entre cultivares y el proteoma de un mismo cultivar

La oferta de durazno en el mercado está restringida a un período muy corto del año, de octubre a marzo. La presencia en el mercado de cada cultivar, varía de 21 a 35 días. Este período se debe a la amplitud de la fecha de cosecha, 1 a 2 semanas y no más de 3 semanas de almacenaje refrigerado. La principal causa de esa corta vida poscosecha es la manifestación de un desorden fisiológico, asociado a la conservación refrigerada, denominado “harinosidad” cuyo síntoma más característico es la disminución de jugosidad. Durante la temporada 2015/2016 evaluó la frecuencia de aparición de síntomas de harinosidad en los cultivares (cvs) Rich Lady, Ginart, Forastero, Flavorcrest, Gold Prince, Aniversario INTA, Opedepe, Flamer Crest, Red Globe, Spring Lady, Don Carlos INTA, Rojo 2 (de dos lotes diferentes) y Elegant Lady. Se plantearon dos objetivos: 1) conocer la aptitud de los cvs para ser utilizados en programas de mejora genética de la EEA INTA San Pedro y 2) identificar mediante MALDI-TOF/TOF diferencias en el proteoma de frutos harinosos y no harinosos, provenientes de un mismo cultivar, temporada y tratamiento. Los frutos de los 13 cvs se colocaron en cámaras a 0°C durante 21 días y luego de 3 o 4 días a 20°C, cuando alcanzaron la madurez organoléptica, se evaluó el contenido aparente de jugo mediante una escala visual de 0 a 5 (0=Sano y 5 Máxima Harinosidad). Los cultivares Don Carlos INTA, Aniversario INTA y Flavorcrest también se evaluaron luego de 28 días a 0°C y 3 o 4 días a 20°C. Se determinó la media, la moda y los porcentajes de frutos en los diferentes grados de harinosidad en la escala visual. Se encontraron diferencias en la sensibilidad al daño por frío entre cultivares, siendo tolerantes Rich Lady, Forastero, Flavorcrest y Ginart. Destacándose el cv Flavorcrest que alcanzó los 28 días con baja harinosidad. Hasta el momento solo se analizó el proteoma del cultivar Spring Lady. En este cultivar, luego de 21 días a 0°C, se detectaron pocos frutos no harinosos y se identificaron un total de 213 proteínas diferencialmente expresadas entre frutos harinosos y no harinosos. Se encontraron importantes diferencias en los metabolismos proteicos, lipídicos y de pared celular. Además se destaca una marcada aparición de enzimas relacionadas a metabolismos secundarios, como la chalcona-flavona isomerasa y la caroteno desaturasa involucradas en la síntesis de flavonoides y carotenos, respectivamente. En contraste se encontró una notoria desaparición de enzimas encargadas del control del estado redox en los frutos harinosos, como la superóxido dismutasa y una glutatión peroxidasa. Esto podría ser el resultado de una respuesta al estrés por frío generado por el tratamiento o una consecuencia del daño ocasionado.EEA San PedroFil: Monti, Laura L. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos; ArgentinaFil: Gabilondo, Julieta. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; ArgentinaFil: Bustamante, Claudia A. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos (CEFOBI); ArgentinaFil: Lara, María V. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos (CEFOBI); ArgentinaFil: Drincovich, María F. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Centro de Estudios Fotosintéticos y Bioquímicos (CEFOBI); ArgentinaFil: Budde, Claudio Olaf. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria San Pedro; Argentin