Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

INTRODUCTION Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets

A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42

Introduction: The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. Methods: We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci forADin 1162 Flanders-BelgianADpatients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (A beta(1-42), T-Tau, P-Tau(181P)). Results: A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE epsilon 4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08-2.58 per unit; P < 1.0e(-15)). Onset age and CSF Ab1-42 decreased with increasing GRS (P-onset_age 5 9.0e(-11); P-A beta = 8.9e(-7)). Discussion: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association

A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid A beta(42)

Introduction: The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. Methods: We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci forADin 1162 Flanders-BelgianADpatients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (A beta(1-42), T-Tau, P-Tau(181P)). Results: A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE epsilon 4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08-2.58 per unit; P <1.0e(-15)). Onset age and CSF Ab1-42 decreased with increasing GRS (P-onset_age 5 9.0e(-11); P-A beta = 8.9e(-7)). Discussion: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND licens

An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer's disease

Mutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer's disease (AD). The influence of other genetic variants in ABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions in ABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in the ABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio = 4.5 (1.3-24.2)], and VNTR length inversely correlated with amyloid beta(1-42) in cerebrospinal fluid and ABCA7 expression. In addition, we identified three novel ABCA7 alternative splicing events. One isoform in particular-which is formed through exon 19 skipping-lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation in ABCA7 to AD

Both common variations and rare non-synonymous substitutions and small insertion/deletions in CLU are associated with increased Alzheimer risk.

BACKGROUND: We have followed-up on the recent genome-wide association (GWA) of the clusterin gene (CLU) with increased risk for Alzheimer disease (AD), by performing an unbiased resequencing of all CLU coding exons and regulatory regions in an extended Flanders-Belgian cohort of Caucasian AD patients and control individuals (n = 1930). Moreover, we have replicated genetic findings by targeted resequencing in independent Caucasian cohorts of French (n = 2182) and Canadian (n = 573) origin and by performing meta-analysis combining our data with previous genetic CLU screenings. RESULTS: In the Flanders-Belgian cohort, we identified significant clustering in exons 5-8 of rare genetic variations leading to non-synonymous substitutions and a 9-bp insertion/deletion affecting the CLU β-chain (p = 0.02). Replicating this observation by targeted resequencing of CLU exons 5-8 in 2 independent Caucasian cohorts of French and Canadian origin identified identical as well as novel non-synonymous substitutions and small insertion/deletions. A meta-analysis, combining the datasets of the 3 cohorts with published CLU sequencing data, confirmed that rare coding variations in the CLU β-chain were significantly enriched in AD patients (OR(MH) = 1.96 [95% CI = 1.18-3.25]; p = 0.009). Single nucleotide polymorphisms (SNPs) association analysis indicated the common AD risk association (GWA SNP rs11136000, p = 0.013) in the 3 combined datasets could not be explained by the presence of the rare coding variations we identified. Further, high-density SNP mapping in the CLU locus mapped the common association signal to a more 5' CLU region. CONCLUSIONS: We identified a new genetic risk association of AD with rare coding CLU variations that is independent of the 5' common association signal identified in the GWA studies. At this stage the role of these coding variations and their likely effect on the β-chain domain and CLU protein functioning remains unclear and requires further studies.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

White Paper: Open Digital Health – accelerating transparent and scalable health promotion and treatment

In this White Paper, we outline recommendations from the perspective of health psychology and behavioural science, addressing three research gaps: (1) What methods in the health psychology research toolkit can be best used for developing and evaluating digital health tools? (2) What are the most feasible strategies to reuse digital health tools across populations and settings? (3) What are the main advantages and challenges of sharing (openly publishing) data, code, intervention content and design features of digital health tools? We provide actionable suggestions for researchers joining the continuously growing Open Digital Health movement, poised to revolutionise health psychology research and practice in the coming years. This White Paper is positioned in the current context of the COVID-19 pandemic, exploring how digital health tools have rapidly gained popularity in 2020-2022, when world-wide health promotion and treatment efforts rapidly shifted from face-to-face to remote delivery. This statement is written by the Directors of the not-for-profit Open Digital Health initiative (n = 6), Experts attending the European Health Psychology Society Synergy Expert Meeting (n = 17), and the initiative consultant, following a two-day meeting (19-20th August 2021).Peer reviewe

Characteristics of Family Dynamics among Japanese Families in Japan

The purpose of this study is to identify family dynamics and their relationships to selected socio-demographic characteristics and mental status among Japanese families in Japan. The Family Dynamics Measure II (FDM II) and a socio-demographic questionnaire were used to obtain data. Participants (n=195; male n=62, female n=129, gender unknown n=4) were obtained from a city, western outskirts of Tokyo. Majority of respondents were married (n=165, 84.6%) and with children (n=128, 65.6%). Family size ranged from 2 to 9 persons (mean= 3.66, SD=1.42). Three-generation families, I.e. presences of grandparent(s), daughter(s)-in-law, and parent(s)-in-law (n=25, 12.8%) were small in numbers. When there were family members ages over 70, female respondents showed negative relations to 4 of 6 dimensions of FDM II. Further, when there were family members ages between 12-17, both male and female respondents showed negative relationships to 3 of 6 dimensions of FDM II. Mental status showed a positive relationship to age of male respondents. Nurses should be aware of relationships between affecting factors and dimensions of family dynamics. The understanding of these gender differences among males and females and the conditions of the family could be quite helpful when advising or counseling family members for betterment of family health

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease

Altres ajuts: The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The research was funded in part by the European Commission Seventh Framework Programme for research, technological development, and demonstration under grant agreement 305299 (AgedBrainSYSBIO), the Belgian Science Policy Office Interuniversity Attraction Poles program, the Alzheimer Research Foundation (SAO-FRA), the Flemish government-initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Flemish government-initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO), the VIB Technology Fund, the University of Antwerp Research Fund, Belgium; European Regional Development Fund, the Italian Ministry of Health (Ricerca Corrente and RF-2010-2319722), and the Fondazione Cassa di Risparmio di Pistoia e Pescia grant (2014.0365).Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets