Contribution of rare variant associations to neurodegenerative disease presentation

Dilliott, Allison A.; Abdelhady, Abdalla; Sunderland, Kelly M; Farhan, Sali M.K.; Abrahão, Agessandro; Binns, Malcolm A.; Black, Sandra E.; Borrie, Michael; Casaubon, Leanne K.; Dowlatshahi, Dar; Finger, Elizabeth; Fischer, Corinne E.; Frank, Andrew; Freedman, Morris; Grimes, David A.; Hassan, Ayman; Jog, Mandar; Kumar, Sanjeev; Kwan, Donna; Lang, Anthony E.; Mandzia, Jennifer; Masellis, Mario; McIntyre, Adam D.; Pasternak, Stephen; Pollock, Bruce G.; Rajji, Tarek K.; Rogaeva, Ekaterina; Sahlas, Demetrios J.; Saposnik, Gustavo; Sato, Christine; Seitz, Dallas; Shoesmith, Christen; Steeves, Thomas; Swartz, Richard H.; Tan, Brian; Tang‐Wai, David F.; Tartaglia, Maria Carmela; Turnbull, John; Zinman, Lorne; Investigators, Ondri; Hegele, Robert A.

doi:10.1038/s41525-021-00243-3

Cited by 18 publications

(21 citation statements)

References 52 publications

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“…Thirdly, neurodegenerative diseases might result from multiple rare variants, each unique in the affected person, and therefore be too rare for selection to have a significant impact. 46 With the increased availability of high-depth next generation sequencing, many rare variants have now been found to be associated with ALS 22 47 48 , Parkinson’s disease 23 49 and Alzheimer’s disease 50 51 , but common variants also contribute to risk. To address these hypotheses of how natural selection may have led to the persistence of common genetic risk variants of neurodegenerative disorders, we used stratified-LDSC to test the relationship between neurodegeneration-related SNPs and SNP-based signatures of natural selection.…”

Section: Discussionmentioning

confidence: 99%

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Chen

Reynolds

Pardiñas

et al. 2022

Preprint

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BackgroundHumans are thought to be more susceptible to neurodegeneration than equivalently-aged primates. It is not known whether this vulnerability is specific to anatomically-modern humans or shared with other hominids. The contribution of introgressed Neanderthal DNA to neurodegenerative disorders remains uncertain. It is also unclear how common variants associated with neurodegenerative disease risk are maintained by natural selection in the population despite their deleterious effects. In this study, we aimed to quantify the genome-wide contribution of Neanderthal introgression and positive selection to the heritability of complex neurodegenerative disorders to address these questions.MethodsWe used stratified-linkage disequilibrium score regression to investigate the relationship between five SNP-based signatures of natural selection, reflecting different timepoints of evolution, and genome-wide associated variants of the three most prevalent neurodegenerative disorders: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.ResultsWe found a significant depletion of positively-selected SNPs in the heritability of Parkinson’s disease, raising the possibility that these variants may modulate disease risk, in addition to conferring an evolutionary advantage. For Alzheimer’s disease and amyotrophic lateral sclerosis, common deleterious disease variants are unlikely to be maintained by positive selection. There was no enrichment of Neanderthal introgression in the SNP-heritability of these disorders, suggesting that Neanderthal admixture is unlikely to have contributed to disease risk.ConclusionsThese findings provide insight into the origins of neurodegenerative disorders within the evolution of Homo sapiens and addresses a long-standing debate, showing that Neanderthal admixture is unlikely to have contributed to common genetic risk of neurodegeneration in anatomically-modern humans.

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Section: Discussionmentioning

confidence: 99%

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Chen

Reynolds

Pardiñas

et al. 2022

Preprint

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“…The other MAPT variant (p.Ala41Thr) occurred in a patient also carrying a pathogenic mutation in the FUS gene (AD#039). Due to the heterogeneity of genetic factors contributing to neurodegeneration, pathogenic/likely pathogenic variants and VUS have been considered as weak allele risk factors ( Dilliott et al, 2021 ). Carriers of these variants were equally distributed between the familial and sporadic groups (Fisher exact test p -value = 1).…”

Section: Resultsmentioning

confidence: 99%

“…In agreement with this hypothesis, Spina et al, 2021, found at least one non-AD neuropathological diagnosis in 98% of patients with EOAD. Due to the heterogeneity of genetic factors contributing to neurodegeneration, and the equal distribution between sporadic and familial forms, we consider pathogenic/hypothetical pathogenic variants and variants with 10.3389/fnagi.2022.969817 uncertain significance in these genes to be weak risk factors (Dilliott et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Dementia-related genetic variants in an Italian population of early-onset Alzheimer’s disease

Bartoletti-Stella

Tarozzi

Mengozzi

et al. 2022

Front. Aging Neurosci.

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Early-onset Alzheimer’s disease (EOAD) is the most common form of early-onset dementia. Although three major genes have been identified as causative, the genetic contribution to the disease remains unsolved in many patients. Recent studies have identified pathogenic variants in genes representing a risk factor for developing Alzheimer’s disease (AD) and in causative genes for other degenerative dementias as responsible for EOAD. To study them further, we investigated a panel of candidate genes in 102 Italian EOAD patients, 45.10% of whom had a positive family history and 21.74% with a strong family history of dementia. We found that 10.78% of patients carried pathogenic or likely pathogenic variants, including a novel variant, in PSEN1, PSEN2, or APP, and 7.84% showed homozygosity for the ε4 APOE allele. Additionally, 7.84% of patients had a moderate risk allele in PSEN1, PSEN2, or TREM2 genes. Besides, we observed that 12.75% of our patients carried only a variant in genes associated with other neurodegenerative diseases. The combination of these variants contributes to explain 46% of cases with a definite familiarity and 32% of sporadic forms. Our results confirm the importance of extensive genetic screening in EOAD for clinical purposes, to select patients for future treatments and to contribute to the definition of overlapping pathogenic mechanisms between AD and other forms of dementia.

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“…Interestingly, we found a high frequency of the p.Arg402Cys variant in the PARK2 gene in the ALS cohort. This variant is classified as a variant of uncertain significance in ClinVar and has been also recently found to be increased in a FTD cohort [ 36 ], where the authors speculated the possible role of the PARK2 gene in the pathogenesis of FTD, highlighting the possible overlap across neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

Vacchiano

Bartoletti-Stella

Rizzo

et al. 2022

Genes

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Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson’s disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis.

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Contribution of rare variant associations to neurodegenerative disease presentation

Cited by 18 publications

References 52 publications

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

The contribution of Neanderthal introgression and natural selection to neurodegenerative diseases

Dementia-related genetic variants in an Italian population of early-onset Alzheimer’s disease

Frequency of Parkinson’s Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study

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