Genome Wide Association Study and Next Generation Sequencing: A Glimmer of Light Toward New Possible Horizons in Frontotemporal Dementia Research

Ciani, Maurizio; Benussi, Luisa; Bonvicini, Cristian; Ghidoni, Roberta

doi:10.3389/fnins.2019.00506

Cited by 23 publications

(27 citation statements)

References 74 publications

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“…It is also of note that General Learning Ability was associated with genetic variations in MAPT, one of the genes in the chromosome 17 locus. Mutations in this gene occur more frequently in patients with frontotemporal dementia (Ciani et al 2019;Strang et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes

Shin¹,

Ma²,

Hofer³

et al. 2020

Cerebral Cortex

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We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.

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Section: Discussionmentioning

confidence: 99%

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes

Shin¹,

Ma²,

Hofer³

et al. 2020

Cerebral Cortex

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“…High-throughput sequencing technologies are particularly useful for the study of complex diseases, mainly opening the door to chase for new genetic players and rare coding variants not considered before [24]. Interestingly, several genetic factors for FTD have been revealed, but a large proportion of FTD cases still has an unidentified genetic origin [10,25].…”

Section: Discussionmentioning

confidence: 99%

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

Ciani

Bonvicini

Scassellati

et al. 2019

IJMS

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Frontotemporal dementia (FTD) is a common form of dementia among early-onset cases. Several genetic factors for FTD have been revealed, but a large proportion of FTD cases still have an unidentified genetic origin. Recent studies highlighted common pathobiological mechanisms among neurodegenerative diseases. In the present study, we investigated a panel of candidate genes, previously described to be associated with FTD and/or other neurodegenerative diseases by targeted next generation sequencing (NGS). We focused our study on sporadic FTD (sFTD), devoid of disease-causing mutations in GRN, MAPT and C9orf72. Since genetic factors have a substantially higher pathogenetic contribution in early onset patients than in late onset dementia, we selected patients with early onset (<65 years). Our study revealed that, in 50% of patients, rare missense potentially pathogenetic variants in genes previously associated with Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis and Lewy body dementia (GBA, ABCA7, PARK7, FUS, SORL1, LRRK2, ALS2), confirming genetic pleiotropy in neurodegeneration. In parallel, a synergic genetic effect on FTD is suggested by the presence of variants in five different genes in one single patient. Further studies employing genome-wide approaches might highlight pathogenic variants in novel genes that explain the still missing heritability of FTD.

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“…The functions of these candidate genes broadly align with the categories identified in the gene set analysis, with the addition of brain function, adult neurogenesis, protein-lipid interactions, and lipid efflux. Two of the novel loci have been previously associated with frontotemporal dementia (FTD) 26 . This signal is not driven by the non-medically verified LOAD cases in the UKB proxy LOAD data ( Supplementary Results ), which suggests that this region is pleiotropic for FTD or contains separate causal variants within the same LD blocks.…”

Section: Discussionmentioning

confidence: 99%

Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

Dp¹,

Ie²,

Je³

et al. 2020

Preprint

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SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.

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Genome Wide Association Study and Next Generation Sequencing: A Glimmer of Light Toward New Possible Horizons in Frontotemporal Dementia Research

Cited by 23 publications

References 74 publications

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes

Global and Regional Development of the Human Cerebral Cortex: Molecular Architecture and Occupational Aptitudes

The Missing Heritability of Sporadic Frontotemporal Dementia: New Insights from Rare Variants in Neurodegenerative Candidate Genes

Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

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