Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan, Badri N.; Barral, Sandra; Jaworski, James; Beecham, Gary W.; Blue, Elizabeth; Tosto, Giuseppe; Reyes‐Dumeyer, Dolly; Medrano, Martin; Lantigua, Rafael; Naj, Adam C.; Thornton, Timothy A.; DeStefano, Anita L.; Martin, Eden R.; Wang, Li‐San; Brown, Lisa; Bush, William S.; Duijn, Cornelia M. van; Goate, Allison; Farrer, Lindsay A.; Haines, Jonathan L.; Boerwinkle, Eric; Schellenberg, Gerard D.; Pericak‐Vance, Margaret A.; Mayeux, Richard

doi:10.1002/acn3.537

Cited by 48 publications

(61 citation statements)

References 51 publications

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“…Notably, several other peaks near the STMN4 gene, including a peak at the STMN4 promoter, displayed significant hypoacetylation. MYRF, a transcription factor which directly activates myelination 62 and has been previously linked to LOAD risk 63 , also displayed strong promoter hypoacetylation (log2FC=-0.48, FDR q=0.03). STMN4 and MYRF also display significantly reduced transcription in qRT-PCR analysis of oligodendrocyte in subjects with AD.…”

Section: Hypoacetylation In Oeg Of the Hippocampusmentioning

confidence: 98%

Cell type-specific histone acetylation profiling of Alzheimer’s Disease subjects and integration with genetics

Ramamurthy

Welch

Cheng

et al. 2020

Preprint

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We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimer's Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) prefer to reside in the microglial histone acetylome, which varies most strongly with age. We observe acetylation differences associated with AD pathology at 3,598 peaks, predominantly in an oligodendrocyte-enriched population. Strikingly, these differences occur at the promoters of known early onset AD (EOAD) risk genes (APP, PSEN1, PSEN2, BACE1), late onset AD (LOAD) risk genes (BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1 and FERMT2), and putative enhancers annotated to other genes associated with AD pathology (MAPT). More broadly, acetylation differences in the oligodendrocyte-enriched population occur near genes in pathways for central nervous system myelination and oxidative phosphorylation. In most cases, these promoter acetylation differences are associated with differences in transcription in oligodendrocytes. Overall, we reveal deregulation of known and novel pathways in AD and highlight genomic regions as therapeutic targets in oligodendrocytes of hippocampus and dlPFC. INTRODUCTION:Alzheimer's Disease (AD) is the most common age-related neurodegenerative disorder 1 . The hallmarks of AD pathology are numerous and include neuronal loss, synaptic dysfunction, gliosis, and the accumulation of intercellular plaques of amyloid-β (Aβ) protein and intracellular neurofibrillary tangles (NFT) of phosphorylated tau protein (MAPT) 2 .Aβ plaques are formed by differential proteolytic cleavage of the amyloid β precursor protein (APP) 3-6 by the α-secretase, β-secretase and γ-secretase enzymes 7 . Studies of individuals affected by early onset (<60 yrs.) familial AD (EOAD) have identified causal autosomal dominant mutations primarily in Aβ processing proteins presenilin-1 (PSEN1) and presenilin-2 (PSEN2), which are part of the γ-secretase complex 8-10 , but also causal mutations or duplications in APP itself [11][12][13] . However, EOAD only accounts for a small minority of AD cases. Late onset sporadic AD (LOAD) is more frequent and accounts for up to 99% or more of AD cases. While increased age is the strongest risk factor and several environmental factors also confer risk for LOAD, its heritability has been estimated to be as high as 79% 14 .In contrast to EOAD, genetic risk for LOAD is less well understood. The ε4 allele comprising mutations in two codons in Apolipoprotein E (APOE) has been identified as the strongest genetic risk factor for LOAD [15][16][17][18][19] . More recently, genome wide association studies (GWAS) 20-27 have reproduced the APOE association and also identified 28 other unique loci harboring genetic variants which increase risk for developing LOAD 26-28 . Strikingly, from the set of most significant (or "sentinel") single nucleotide polymorphisms (SNPs) derived from GWAS and SNPs in strong linkage...

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Section: Hypoacetylation In Oeg Of the Hippocampusmentioning

confidence: 98%

Cell type-specific histone acetylation profiling of Alzheimer’s Disease subjects and integration with genetics

Ramamurthy

Welch

Cheng

et al. 2020

Preprint

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“…Indeed, recent results have provided insight into disease susceptibility (1), treatment response (2), development of desirable traits in animals (3) and crop plants (4) and understanding population genetics in many species (5). Human genetics study designs in particular are transitioning from targeting a handful of candidate genes to full exome or genome sequencing to find trait-associated loci in individuals, families or populations (6, 7). In all study designs, sites of genome variation alone are insufficient to draw conclusions.…”

Section: Introductionmentioning

confidence: 99%

Ensembl variation resources

et al. 2018

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The major goal of sequencing humans and many other species is to understand the link between genomic variation, phenotype and disease. There are numerous valuable and well-established variation resources, but collating and making sense of non-homogeneous, often large-scale data sets from disparate sources remains a challenge. Without a systematic catalogue of these data and appropriate query and annotation tools, understanding the genome sequence of an individual and assessing their disease risk is impossible. In Ensembl, we substantially solve this problem: we develop methods to facilitate data integration and broad access; aggregate information in a consistent manner and make it available a variety of standard formats, both visually and programmatically; build analysis pipelines to compare variants to comprehensive genomic annotation sets; and make all tools and data publicly available.

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“…These two variants were also identified in individual Caribbean Hispanic LOAD cases 80 . One of these two variants, the p.Arg434Trp, was reported in affected individuals from two large Caribbean Hispanic LOAD families 80 . It is important to note that segregation was not shown for this variant, with absence in some affected individuals and presence in potentially presymptomatic individuals who were younger than the usual AAO of other family members.…”

Section: Discovery Of New Ad Risk Variants In Understudied Populationsmentioning

confidence: 99%

“…Taken together this data argues against a fully penetrant mode for AKAP9 mutations in this Caribbean Hispanic family. Moreover, 4 other AKAP9 variants were reported in Caribbean Hispanic families, with 3 of them present in the same family 80 . Two different AKAP9 variants have subsequently been reported in LOAD families of European ancestry, although segregation was not shown for either of them 81 .…”

Section: Discovery Of New Ad Risk Variants In Understudied Populationsmentioning

confidence: 99%

How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

Dehghani

Brás

Guerreiro

2020

Preprint

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The majority of genome-wide association studies have been conducted using samples with a European genetic background. As a field, we acknowledge this limitation and the need to increase the diversity of populations studied. A major challenge when designing and conducting such studies is to assimilate large samples sizes so that we attain enough statistical power to detect variants associated with disease, particularly when trying to identify variants with low and rare minor allele frequencies. In this study, we aimed to illustrate the benefits, to genetic characterization of Alzheimer's disease (AD), in researching currently understudied populations. This is important for both fair representation of world populations and the translatability of findings. To that end, we have conducted a literature search to understand the contributions of studies, on different populations, to AD genetics. We systematically quantified the number of studies identifying mutations in known disease-causing genes, in a world-wide manner, and discussed the contributions of research in understudied populations to the identification of novel genetic factors in this disease. Additionally, we compared the effects of genome-wide significant SNPs across populations by focusing on loci that show different association profiles between populations (a key example being APOE). This work functions to both highlight how understudied populations have furthered our understanding of AD genetics, and to help us gage our progress in understanding the genetic architecture of this disease in all populations.

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Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Cited by 48 publications

References 51 publications

Cell type-specific histone acetylation profiling of Alzheimer’s Disease subjects and integration with genetics

Cell type-specific histone acetylation profiling of Alzheimer’s Disease subjects and integration with genetics

Ensembl variation resources

How understudied populations have contributed to our understanding of Alzheimer’s disease genetics

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