Reverse Engineering of Modified Genes by Bayesian Network Analysis Defines Molecular Determinants Critical to the Development of Glioblastoma

In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I–IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96–100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential ‘hubs of activity’. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several ‘key genes’ may be required for the development of glioblastoma. Further studies are needed to validate these ‘key genes’ as useful tools for early detection and novel therapeutic options for these tumors

Increased Risk of Childhood Brain Tumors Among Children Whose Parents Had Farm-Related Pesticide Exposures During Pregnancy

Malignant brain tumors rank second in both incidence and mortality by cancer in children, and they are the leading cause of cancer death in children. Relatively little is known about the etiology of childhood brain tumor (CBT). While there are several studies which link pesticide exposure to increased risk of CBT, findings have been inconsistent. We performed a meta-analysis on 15 published epidemiological studies to test that in utero exposure to pesticides may be involved in the development of brain cancer in children. Meta-analysis was performed using the general variance-based method and homogeneity was tested by means of the Q statistic. Summary relative risk (RR) estimates were calculated for childhood brain cancer from (1) paternal exposure to pesticides prior to conception, (2) both maternal and paternal exposure to pesticides during pregnancy, (3) maternal exposure during pregnancy to: (a) agricultural and (b) non-agricultural activities, and (4) childhood exposure to: (a) agricultural and (b) nonagricultural activities up to date of diagnosis with CBT. The comparative toxicogenomics database (CTD) was used to identify gene-pesticide-CBT interactions. Findings of meta-analyses revealed a significantly increased risk of CBT among children whose mothers had farm-related exposures during pregnancy (RR=1.48, 95% CI=1.18–1.84). A dose response was recognized when this risk estimate was compared to those for risk of CBT from maternal exposure to non-agricultural pesticides (e.g., home extermination, pest strips) during pregnancy (RR=1.36, 1.10–1.68), and risk of CBT among children exposed to agricultural activities (RR=1.32, 1.04–1.67). Three studies combined for the paternal exposure to pesticides during preconception produced a calculated summary risk estimate of odds ratio (OR) = 2.29 (95% CI: 1.39–3.78). Meta-analysis of five studies of paternal exposure to pesticides during pregnancy produced a final calculated summary risk estimate of OR = 1.63 (95% CI: 1.16–2.31). The search of the CTD databases revealed association between herbicide and astrocytoma and more than 300 genes are altered by exposure to herbicide, fungicide, insecticide or pesticides. In summary, comparing results from our categories of exposure, preconception and pregnancy exposure estimates were slightly higher than childhood exposure estimates, paternal exposures produced slightly higher risk estimates compared to maternal exposures, agricultural exposures produced slightly higher risk estimates compared to non-agricultural exposures and CTD search revealed potential genes-pesticides-astrocytoma interactions. Based on the collective results of these meta-analyses, it appears that pesticide exposure may increase risk of CBT, with preconception and prenatal exposures being especially important factors in increasing risk of its development. Interestingly, paternal exposure may be as important, if not more important than maternal exposures, particularly during the preconception period. Whether this is a result of paternal exposures being more prevalent than maternal exposures or the consequence of a biological process, is a question that deserves further attention in future investigations of CBT etiology

Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer's disease

INTRODUCTION: We performed linkage analyses in Caribbean Hispanic families with multiple late-onset Alzheimer's disease (LOAD) cases to identify regions that may contain disease causative variants. METHODS: We selected 67 LOAD families to perform genome-wide linkage scan. Analysis of the linked regions was repeated using the entire sample of 282 families. Validated chromosomal regions were analyzed using joint linkage and association. RESULTS: We identified 26 regions linked to LOAD (HLOD ≥3.6). We validated 13 of the regions (HLOD ≥2.5) using the entire family sample. The strongest signal was at 11q12.3 (rs2232932: HLODmax = 4.7, Pjoint = 6.6 × 10(-6)), a locus located ∼2 Mb upstream of the membrane-spanning 4A gene cluster. We additionally identified a locus at 7p14.3 (rs10255835: HLODmax = 4.9, Pjoint = 1.2 × 10(-5)), a region harboring genes associated with the nervous system (GARS, GHRHR, and NEUROD6). DISCUSSION: Future sequencing efforts should focus on these regions because they may harbor familial LOAD causative mutations

The Grizzly, December 4, 1981

Dealing With Financial Pressure • EcBA Department Interviews for New Positions • Freshman Relates Pre-Collegiate Experiences in Japan • Union Evaluation Prompts Improvement • Campus-wide Planning Meeting Sets Competitive Goals for UC • Residents Fix Up Curtis Hall • Lucas Named To PaCIE • \u27Messiah\u27 Rehearsal Open to Public • Jarvis and Rutherford in Last Coffeehouse • Best Albums of 1981 • Senior Poet Honored Nationally • New Wrestlers Lead the Way • Girls B-Ball Prime for Opener • Baseball Team Has New Skipper • Men\u27s Swimmers Take Third Place • Hoopsters Off to Slow Start • Gymnasts Pleasing • Women\u27s Swim Team Prepares for Tough Schedule • Mike Fagan All-MAChttps://digitalcommons.ursinus.edu/grizzlynews/1069/thumbnail.jp

The Grizzly, February 25, 1983

USGA Plans Communication Revision • Foley, D\u27Alesio First Place Winners at Talent Show • College Union Holds Tenth Anniversary • Ritter Production Opens: Skin of Our Teeth • Mass is Popular: Newman Society Links U.C. • Small Heads Alcohol Committee • SPC Seeks Editors • Union Calendar • Grizzly Looks For New Business Manager • Winterfest 1983: International Desserts Festival Tonight • Winterfest Schedule • Letters to the Editor: Admissions Dean Corrects Errors; Hoop Club President Responds; Student Reacts Negatively • Social Life at Ursinus Should be Improved • In the Gates • Registrar Announces Pre-Registration • President\u27s Corner • Roving Reporter: Do You Think the New Alcohol Policy Proposed by the Administration was the Correct Way to Handle the Situations That Occurred on Campus? • Bears Drown Monarchs • Women\u27s Swimming Ends 10-1 • MAC Competition: Wrestlers Take Seventh • Gymnasts Move up a Rank • Lady Hoopsters Finish With Victoryhttps://digitalcommons.ursinus.edu/grizzlynews/1095/thumbnail.jp

The Grizzly, October 22, 1982

Ferry Named Ursinus Queen • Unique Course Offered • U.C. Choir Presents Bach • Night School Enrollment Up • 1983 Spring Registration • Letters to the Editor • President\u27s Corner • Lewis on Wall Street • Half a Great Show • Watching the Boob Tube • Homecoming \u2782 • And to Prove My Point • New Bus Schedule • Washington Semester: Get Out of Here • Bear Pack Falls to Stiff Competition • Soccer Conquers Albright and Alumni • Grapplers Take to the Mats • Grizzlies Suffer Homecoming Setback • Delaware tops Lady Bearshttps://digitalcommons.ursinus.edu/grizzlynews/1085/thumbnail.jp

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation

Correction: Volume: 25 Issue: 8 Pages: 1901-1903 DOI: 10.1038/s41380-019-0529-7The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- andAPOEbased risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes:IGHG3(p = 9.8 x 10(-7)), an immunoglobulin gene whose antibodies interact with beta-amyloid, a long non-coding RNAAC099552.4(p = 1.2 x 10(-7)), and a zinc-finger proteinZNF655(gene-based p = 5.0 x 10(-6)). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.Peer reviewe

Alzheimer’s disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals

Background: Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. Methods: Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. Results: In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. Conclusions: These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics

SORL1 mutations in early- and late-onset Alzheimer disease.

OBJECTIVE: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor (SORL1) gene. METHODS: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with SORL1 mutations were characterized based on clinical reviews of medical records. Functional studies were completed to evaluate β-amyloid (Aβ) production and amyloid precursor protein (APP) trafficking associated with SORL1 mutations. RESULTS: SORL1 alterations were present in 2 EOAD families. In one, a SORL1 T588I change was identified in 4 individuals with AD, 2 of whom had parkinsonian features. In the second, an SORL1 T2134 alteration was found in 3 of 4 AD cases, one of whom had postmortem Lewy bodies. Among LOAD cases, 4 individuals with either SORL1 A528T or T947M alterations had parkinsonian features. Functionally, the variants weaken the interaction of the SORL1 protein with full-length APP, altering levels of Aβ and interfering with APP trafficking. CONCLUSIONS: The findings from this study support an important role for SORL1 mutations in AD pathogenesis by way of altering Aβ levels and interfering with APP trafficking. In addition, the presence of parkinsonian features among select individuals with AD and SORL1 mutations merits further investigation