Alzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, ...with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus. In 2013, the International Genomics of Alzheimer's Project (IGAP) did a meta-analysis of all existing GWAS using data from 74 046 individuals, which stood as the largest Alzheimer's disease GWAS until 2018. This meta-analysis discovered 19 susceptibility loci for Alzheimer's disease in populations of European ancestry.
Three new Alzheimer's disease GWAS published in 2018 and 2019, which used larger sample sizes and proxy phenotypes from biobanks, have substantially increased the number of known susceptibility loci in Alzheimer's disease to 40. The first, an updated GWAS from IGAP, included 94 437 individuals and discovered 24 susceptibility loci. Although IGAP sought to increase sample size by recruiting additional clinical cases and controls, the two other studies used parental family history of Alzheimer's disease to define proxy cases and controls in the UK Biobank for a genome-wide association by proxy, which was meta-analysed with data from GWAS of clinical Alzheimer's disease to attain sample sizes of 388 324 and 534 403 individuals. These two studies identified 27 and 29 susceptibility loci, respectively. However, the three studies were not independent because of the large overlap in their participants, and interpretation can be challenging because different variants and genes were highlighted by each study, even in the same locus. Furthermore, neither the variant with the strongest Alzheimer's disease association nor the nearest gene are necessarily causal. This situation presents difficulties for experimental studies, drug development, and other future research.
The ultimate goal of understanding the genetic architecture of Alzheimer's disease is to characterise novel biological pathways that underly Alzheimer's disease pathogenesis and to identify novel drug targets. GWAS have successfully contributed to the characterisation of the genetic architecture of Alzheimer's disease, with the identification of 40 susceptibility loci; however, this does not equate to the discovery of 40 Alzheimer's disease genes. To identify Alzheimer's disease genes, these loci need to be mapped to variants and genes through functional genomics studies that combine annotation of variants, gene expression, and gene-based or pathway-based analyses. Such studies are ongoing and have validated several genes at Alzheimer's disease loci, but greater sample sizes and cell-type specific data are needed to map all GWAS loci.
Short open reading frames (sORFs) are a common feature of all genomes, but their coding potential has mostly been disregarded, partly because of the difficulty in determining whether these sequences ...are translated. Recent innovations in computing, proteomics and high-throughput analyses of translation start sites have begun to address this challenge and have identified hundreds of putative coding sORFs. The translation of some of these has been confirmed, although the contribution of their peptide products to cellular functions remains largely unknown. This Review examines this hitherto overlooked component of the proteome and considers potential roles for sORF-encoded peptides.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
GWAS summary statistics are fundamental for a variety of research applications yet no common storage format has been widely adopted. Existing tabular formats ambiguously or incompletely store ...information about genetic variants and associations, lack essential metadata and are typically not indexed yielding poor query performance and increasing the possibility of errors in data interpretation and post-GWAS analyses. To address these issues, we adapted the variant call format to store GWAS summary statistics (GWAS-VCF) and developed open-source tools to use this format in downstream analyses. We provide open access to over 10,000 complete GWAS summary datasets converted to this format ( https://gwas.mrcieu.ac.uk ).
Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer’s disease (AD) risk. In particular, AD risk alleles primarily affect ...the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches.
Romero-Molina, Garretti, and colleagues illustrate their hypothesis that genetic variants associated with AD modulate disease susceptibility by affecting genes and pathways that play critical roles in efferocytosis, the phagocytic clearance of cholesterol-rich cellular debris by macrophages like microglia.
Background
Mitochondria regulate energy and metabolic homeostasis, with increasing evidence implicating mitochondrial dysfunction in Alzheimer’s disease (AD) pathogenesis. Each mitochondrion contains ...multiple copies of the mitochondrial genome (mtDNA), with mtDNA copy number (mtDNAcn) been used as a surrogate measure of mitochondrial function. Here we evaluate the association of mtDNAcn with neuropathological diagnosis of AD and evaluate shared genetic etiology between AD and mtDNAcn.
Methods
We evaluated the association of mtDNAcn with a neuropathological diagnosis of AD in 1194 non‐Hispanic white subjects (cases = 706, controls = 468) from three cohorts (ROSMAP, MSBB, Mayo) from the Accelerating Medicines Partnership Alzheimer’s disease (AMP‐AD). Relative mtDNAcn was estimated as the ratio of mtDNA to nuclear DNA using whole genome sequencing data from DNA isolated from brain tissue. Neuropathological AD was determined based on neuropathological burden of amyloid plaques and tangles. Logistic regression adjusting for mitochondrial haplogroup, age of death, sex, APOE, post‐mortem interval and source tissue was used to evaluate the association of mtDNAcn with AD in each cohort separately and jointly in an inverse weighted fixed‐effects meta‐analysis (IVW FE). Additionally, we estimated the genetic correlation between mtDNAcn and AD, evaluated the association of a mtDNAcn polygenic risk score (PRS) with clinical AD (cases = 13312, controls = 13119), and conducted bidirectional two‐sample Mendelian randomization to estimate the causal relationship between mtDNAcn and AD.
Results
Higher mtDNAcn was associated with a reduced risk of neuropathological AD (IVW FE: OR95%CI = 0.70 0.58, 0.84. mtDNAcn was not genetically correlated with AD (rg = 0.13 (0.16), p = 0.4) and a mtDNAcn PRS was not associated with clinical AD (OR95%CI = 1 0.97, 1.03, p = 0.884). Mendelian randomization did not support a causal relationship between mtDNAcn and AD (OR95%CI = 0.93 0.74, 1.14, p = 0.46).
Conclusion
Elevated mtDNAcn estimated from brain tissue was associated with a reduced risk of neuropathological AD, suggesting that mitochondrial dysfunction is associated with AD pathogenesis. However, genetically predicted mtDNAcn estimated from peripheral blood was not associated with AD using genetically informed approaches. As such, further research is needed to determine if mitochondrial dysfunction causes, mediates, or is a by‐product of AD pathogenesis.
Mild behavioral impairment (MBI) describes the emergence of later‐life neuropsychiatric symptoms (NPS) as an at‐risk state for incident cognitive decline and dementia, and for some as a potential ...manifestation of prodromal dementia. How NPS mechanistically link to the development of mild cognitive impairment and Alzheimer's disease (AD) is not fully understood, with potential mechanisms including shared risk factors related to both NPS and cognitive impairment, or AD pathology promoting NPS. This is the first exploratory study to examine whether AD genetic loci as a genetic risk score (GRS), or individually, are a shared risk factor with MBI. Participants were 1,226 older adults (aged 72–79; 738 males; 763 normal cognition) from the Personality and Total Health Through Life project. MBI was approximated in accordance with Criterion 1 of the ISTAART‐AA diagnostic criteria using a transformation algorithm for the neuropsychiatric inventory. A GRS was constructed from 25 AD risk loci. Binomial logistic regression adjusting for age, gender, and education examined the association between GRS and MBI. A higher GRS and APOE*ε4 were associated with increased likelihood of affective dysregulation. Nominally significant associations were observed between MS4A4A‐rs4938933*C and MS4A6A‐rs610932*G with a reduced likelihood of affective dysregulation; ZCWPW1‐rs1476679*C with a reduced likelihood of social inappropriateness and abnormal perception/thought content; BIN1‐rs744373*G and EPHA1‐rs11767557*C with higher likelihood of abnormal perception/thought content; NME8‐rs2718058*G with a reduced likelihood of decreased motivation. These preliminary findings suggest a common genetic etiology between MBI and traditionally recognized cognitive problems observed in AD and improve our understanding of the pathophysiological features underlying MBI.
Observational studies have suggested that light-to-moderate alcohol consumption decreases the risk of Alzheimer's disease, but it is unclear if this association is causal.
Two-sample Mendelian ...randomization (MR) analysis was used to examine whether alcohol consumption, alcohol dependence, or Alcohol Use Disorder Identification Test (AUDIT) scores were causally associated with the risk of Late-Onset Alzheimer's disease (LOAD) or Alzheimer's disease age of onset survival (AAOS). Additionally, γ-glutamyltransferase levels were included as a positive control.
There was no evidence of a causal association between alcohol consumption, alcohol dependence, or AUDIT, and LOAD. Alcohol consumption was associated with an earlier AAOS and increased γ-glutamyltransferase blood concentrations. Alcohol dependence was associated with a delayed AAOS.
MR found robust evidence of a causal association between alcohol consumption and an earlier AAOS, but not alcohol intake and LOAD risk. The protective effect of alcohol dependence is potentially due to survivor bias.
•We evaluated causal relationships between alcohol intake and Alzheimer's disease•Alcohol consumption is causally associated with an earlier Alzheimer's disease age of onset•No evidence of causal associations between alcohol intake and Alzheimer's disease risk
Epidemiological research has suggested that inhibition of tumor necrosis factor (TNF)-α in patients with rheumatoid arthritis (RA) reduces the overall risk of Alzheimer's disease (AD). TNF-α ...antagonists have been suggested as a potential treatment for AD. We used a two-sample Mendelian randomization design to examine the causal relationship between blood TNF expression, serum TNF-α levels, and RA on AD risk. Our results do not support a causal relationship between TNF expression, serum TNF-α levels, and RA on AD risk.
Physical activity may preserve cognitive function in older adults, but benefits vary by sex and genetic factors.
We tested the longitudinal association between physical activity and cognitive ...performance to de termine whether a common genetic polymorphism for brain-derived neurotrophic factor (BDNF Val66Met) moderated this effect.
In a 12-year longitudinal population-based sample of older adults (n = 2,218), we used growth curve modeling to investigate whether the benefits of physical activity on cognitive preservation differed by BDNF genotype and sex across multiple cognitive domains including processing speed, attention, working memory, and episodic verbal memory.
The relationship between physical activity and cognitive performance was dependent on BDNF carrier status in males (Δχ2 Δdf = 12.94 4, p = 0.01), but not in females (Δχ2 Δdf = 4.38 4, p = 0.36). Cognition benefited from physical activity in male BDNF met noncarriers, but not met carriers, whereas cognition was not statistically significantly related to physical activity in females regardless of genotype.
We observed longitudinal, but not cross-sectional, effects of physical activity on cognitive performance. Our study highlights the importance of longitudinal follow-up and consideration of sex differences in the relationships between physical activity, BDNF genotype, and cognitive decline. The findings contribute to understanding gene-lifestyle interactions in promoting cognitive health.
Genome-wide association studies (GWAS) have indicated moderate genetic overlap between Alzheimer's disease (AD) and related dementias (ADRD), Parkinson's disease (PD) and amyotrophic lateral ...sclerosis (ALS), neurodegenerative disorders traditionally considered etiologically distinct. However, the specific genetic variants and loci underlying this overlap remain almost entirely unknown.
We leveraged state-of-the-art GWAS for ADRD, PD, and ALS. For each pair of disorders, we examined each of the GWAS hits for one disorder and tested whether they were also significant for the other disorder, applying Bonferroni correction for the number of variants tested. This approach rigorously controls the family-wise error rate for both disorders, analogously to genome-wide significance.
Eleven loci with GWAS hits for one disorder were also associated with one or both of the other disorders: one with all three disorders (the MAPT/KANSL1 locus), five with ADRD and PD (near LCORL, CLU, SETD1A/KAT8, WWOX, and GRN), three with ADRD and ALS (near GPX3, HS3ST5/HDAC2/MARCKS, and TSPOAP1), and two with PD and ALS (near GAK/TMEM175 and NEK1). Two of these loci (LCORL and NEK1) were associated with an increased risk of one disorder but decreased risk of another. Colocalization analysis supported a shared causal variant between ADRD and PD at the CLU, WWOX, and LCORL loci, between ADRD and ALS at the TSPOAP1 locus, and between PD and ALS at the NEK1 and GAK/TMEM175 loci. To address the concern that ADRD is an imperfect proxy for AD and that the ADRD and PD GWAS have overlapping participants (nearly all of which are from the UK Biobank), we confirmed that all our ADRD associations had nearly identical odds ratios in an AD GWAS that excluded the UK Biobank, and all but one remained nominally significant (p < 0.05) for AD.
In one of the most comprehensive investigations to date of pleiotropy between neurodegenerative disorders, we identify eleven genetic risk loci shared among ADRD, PD, and ALS. These loci support lysosomal/autophagic dysfunction (GAK/TMEM175, GRN, KANSL1), neuroinflammation/immunity (TSPOAP1), oxidative stress (GPX3, KANSL1), and the DNA damage response (NEK1) as transdiagnostic processes underlying multiple neurodegenerative disorders.
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