Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus

Rajabli, Farid; Feliciano‐Astacio, Briseida E.; Cukier, Holly N.; Wang, Liyong; Griswold, Anthony J.; Hamilton‐Nelson, Kara L.; Adams, Larry D.; Rodríguez, Vanessa; Mena, Pedro; Tejada, Sergio; Celis, Katrina; Whitehead, Patrice L.; Booven, Derek J. Van; Hofmann, Natalia K.; Bussies, Parker L.; Prough, Michael; Chinea, Ángel; Feliciano, Nereida I.; Vardarajan, Badri N.; Reitz, Christiane; Lee, Joseph H.; Prince, Martin; I, Jiménez; Mayeux, Richard; Acosta, Heriberto; Dalgard, Clifton L.; Haines, Jonathan L.; Vance, Jeffery M.; Cuccaro, Michael L.; Beecham, Gary W.; Pericak‐Vance, Margaret A.

doi:10.1016/j.neurobiolaging.2021.02.019

Cited by 4 publications

(4 citation statements)

References 47 publications

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“…Samples from Ibadan and PR had WGS performed at the Uniformed Services University of the Health Sciences (USUHS) using standard protocols as previously described [29]. Illumina's HiSeq Alignment Software (HAS) was used to analyze the data including alignment to the GRCh38 reference genome with the Issac aligner [30] and variant calling with Strelka [31].…”

Section: Study Samplesmentioning

confidence: 99%

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry

et al. 2022

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African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (β = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (β = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (β = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the “protective” direction but failing to pass a 0.05 significance threshold (β = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

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Section: Study Samplesmentioning

confidence: 99%

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry

et al. 2022

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“…Homozygous and compound heterozygous VWA2 mutations mimic autosomal recessive inheritance in sporadic AD cases 34 . A missense variant p.Asp238Glu in UNC13B showed segregation within two families of Puerto Rican ancestry and was overrepresented in the AD cases 35 .…”

Section: Alzheimer's Diseasementioning

confidence: 96%

Intervention of next-generation sequencing in diagnosis of Alzheimer’s disease: challenges and future prospects

Chandy

2023

Dement. neuropsychol.

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Clinical diagnosis of several neurodegenerative disorders based on clinical phenotype is challenging due to its heterogeneous nature and overlapping disease manifestations. Therefore, the identification of underlying genetic mechanisms is of paramount importance for better diagnosis and therapeutic regimens. With the emergence of next-generation sequencing, it becomes easier to identify all gene variants in the genome simultaneously, with a system-wide and unbiased approach. Presently various bioinformatics databases are maintained on discovered gene variants and phenotypic indications are available online. Since individuals are unique in their genome, evaluation based on their genetic makeup helps evolve the diagnosis, counselling, and treatment process at the personal level. This article aims to briefly summarize the utilization of next-generation sequencing in deciphering the genetic causes of Alzheimer’s disease and address the limitations of whole genome and exome sequencing.

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“…Several genetic variants (e.g., the unc-13 homolog B gene) in chromosome 9 have been suggested to be connected with the risk of LOAD in whole-genome sequencing and parametric linkage analyses [ 91 ]. SNP analysis of DAPK1 , which is also localized on chromosome 9, has identified two variants, rs4878104 and rs4877365, that are potentially connected with LOAD in several sample cohorts [ 36 ].…”

Section: Dapk1 and Admentioning

confidence: 99%

Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

Zhang,

Kim,

Lee

2024

Transl Neurodegener

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Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly and represents a major clinical challenge in the ageing society. Neuropathological hallmarks of AD include neurofibrillary tangles composed of hyperphosphorylated tau, senile plaques derived from the deposition of amyloid-β (Aβ) peptides, brain atrophy induced by neuronal loss, and synaptic dysfunctions. Death-associated protein kinase 1 (DAPK1) is ubiquitously expressed in the central nervous system. Dysregulation of DAPK1 has been shown to contribute to various neurological diseases including AD, ischemic stroke and Parkinson’s disease (PD). We have established an upstream effect of DAPK1 on Aβ and tau pathologies and neuronal apoptosis through kinase-mediated protein phosphorylation, supporting a causal role of DAPK1 in the pathophysiology of AD. In this review, we summarize current knowledge about how DAPK1 is involved in various AD pathological changes including tau hyperphosphorylation, Aβ deposition, neuronal cell death and synaptic degeneration. The underlying molecular mechanisms of DAPK1 dysregulation in AD are discussed. We also review the recent progress regarding the development of novel DAPK1 modulators and their potential applications in AD intervention. These findings substantiate DAPK1 as a novel therapeutic target for the development of multifunctional disease-modifying treatments for AD and other neurological disorders.

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Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus

Cited by 4 publications

References 47 publications

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s Disease in African Ancestry

Intervention of next-generation sequencing in diagnosis of Alzheimer’s disease: challenges and future prospects

Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

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