Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets

Zhang, Ming; Dilliott, Allison A.; Khallaf, Roaa; Robinson, John F.; Hegele, Robert A.; Comishen, Michael; Sato, Christine; Tosto, Giuseppe; Reitz, Christiane; Mayeux, Richard; George‐Hyslop, Peter St; Freedman, Morris; Rogaeva, Ekaterina

doi:10.1093/brain/awz289

Cited by 11 publications

(15 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The methylome-wide profiles of identical vs fraternal siblings illustrated that DNAm levels are under strong genetic control. 69,73 Hence, genetic differences could lead to the incorrect interpretation of age predictions and health outcomes. For instance, genetic variability partially accounts for the variance in DNAm PhenoAge, 14 and ethnic differences could affect the aging rate of the Horvath clock.…”

Section: Confounders Of Dnam Clock Accuracymentioning

confidence: 99%

“…In contrast, the triplet’s offspring with early-onset AD (at age 50) had a DNAm-age 9 years older than chronological age, indicating accelerated aging. 73…”

Section: Studies Of Dnam Clocks In Neurodegenerative Diseasesmentioning

confidence: 99%

“…In contrast, the triplet's offspring with early-onset AD (at age 50) had a DNAm-age 9 years older than chronological age, indicating accelerated aging. 73 Acceleration of the Horvath clock was also linked to PD, and an association was observed between PD and DNAmbased measures of blood cell types (patients showed more granulocytes but fewer helper T and B cells than controls). 16 Furthermore, investigation of a PD family with the p.A53E mutation in α-synuclein showed that an earlier onset was accompanied by increased DNAm-age acceleration.…”

Section: Studies Of Dnam Clocks In Neurodegenerative Diseasesmentioning

confidence: 99%

See 2 more Smart Citations

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

2020

Self Cite

View full text Add to dashboard Cite

The number of age predictors based on DNA methylation (DNAm) profile is rising due to their potential in predicting healthspan and application in age-related illnesses, such as neurodegenerative diseases. The cumulative assessment of DNAm levels at age-related CpGs (DNAm clock) may reflect biological aging. Such DNAm clocks have been developed using various training models and could mirror different aspects of disease/aging mechanisms. Hence, evaluating several DNAm clocks together may be the most effective strategy in capturing the complexity of the aging process. However, various confounders may influence the outcome of these age predictors, including genetic and environmental factors, as well as technical differences in the selected DNAm arrays. These factors should be taken into consideration when interpreting DNAm clock predictions. In the current review, we discuss 15 reported DNAm clocks with consideration for their utility in investigating neurodegenerative diseases and suggest research directions towards developing a more optimal measure for biological aging.

show abstract

Section: Confounders Of Dnam Clock Accuracymentioning

confidence: 99%

“…In contrast, the triplet’s offspring with early-onset AD (at age 50) had a DNAm-age 9 years older than chronological age, indicating accelerated aging. 73…”

Section: Studies Of Dnam Clocks In Neurodegenerative Diseasesmentioning

confidence: 99%

Section: Studies Of Dnam Clocks In Neurodegenerative Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…DNAm-age of the triplets was 6–10 years younger than chronological age. In contrast, DNAm-age was 9 years older in the offspring with EOAD, suggesting accelerated aging [ 84 ]. However, it is not clear if acceleration of DNAm-age causes aging or reacts to aging, which could be addressed in future longitudinal studies of DNAm clocks.…”

Section: Genetics Of Eoadmentioning

confidence: 99%

Early-Onset Alzheimer’s Disease: What Is Missing in Research?

Ayodele

Rogaeva

Kurup

et al. 2021

Curr Neurol Neurosci Rep

Self Cite

122

View full text Add to dashboard Cite

Purpose of Review Early-onset Alzheimer’s disease (EOAD), defined as Alzheimer’s disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward. Recent Findings EOAD cases make up 5–10% of AD cases but only 10–15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear. Summary While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.

show abstract

“…In general, DNAm levels at certain GpGs could be modified by genetic factors. The strong genetic control of DNAm is evident by the very similar methylome pattern in identical twins/triplets vs fraternal siblings [ 33 , 37 ]. A specific example is increased DNAm at the C9orf72 locus in response to a G 4 C 2 -expansion, which correlates with disease duration and age of onset [ 14 , 27 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

Combined epigenetic/genetic study identified an ALS age of onset modifier

Zhang

Sáez-Atiénzar

et al. 2021

acta neuropathol commun

Self Cite

View full text Add to dashboard Cite

Age at onset of amyotrophic lateral sclerosis (ALS) is highly variable (eg, 27–74 years in carriers of the G4C2-expansion in C9orf72). It might be influenced by environmental and genetic factors via the modulation of DNA methylation (DNAm) at CpG-sites. Hence, we combined an epigenetic and genetic approach to test the hypothesis that some common single nucleotide polymorphisms (SNPs) at CpG-sites (CpG-SNPs) could modify ALS age of onset. Our genome-wide DNAm analysis suggested three CpG-SNPs whose DNAm levels are significantly associated with age of onset in 249 ALS patients (q < 0.05). Next, genetic analysis validated the association of rs4970944 with age of onset in the discovery (n = 469; P = 0.025) and replication (n = 4160; P = 0.007) ALS cohorts. A meta-analysis of the cohorts combined showed that the median onset in AA-carriers is two years later than in GG-carriers (n = 4629; P = 0.0012). A similar association was observed with its tagging SNPs, implicating a 16 Kb region at the 1q21.3 locus as a modifier of ALS age of onset. Notably, rs4970944 genotypes are also associated with age of onset in C9orf72-carriers (n = 333; P = 0.025), suggesting that each A-allele delays onset by 1.6 years. Analysis of Genotype-Tissue Expression data revealed that the protective A-allele is linked with the reduced expression of CTSS in cerebellum (P = 0.00018), which is a critical brain region in the distributed neural circuits subserving motor control. CTSS encodes cathepsin S protein playing a key role in antigen presentation. In conclusion, we identified a 16 Kb locus tagged by rs4970944 as a modifier of ALS age of onset. Our findings support the role of antigen presenting processes in modulating age of onset of ALS and suggest potential drug targets (eg, CTSS). Future replication studies are encouraged to validate the link between the locus tagged by rs4970944 and age of onset in independent ALS cohorts, including different ethnic groups.

show abstract

Genetic and epigenetic study of an Alzheimer’s disease family with monozygotic triplets

Cited by 11 publications

References 32 publications

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

Early-Onset Alzheimer’s Disease: What Is Missing in Research?

Combined epigenetic/genetic study identified an ALS age of onset modifier

Contact Info

Product

Resources

About