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000283156 1001_ $$aMirza, Saira S$$b0
000283156 1112_ $$aAlzheimer’s Association International Conference$$cToronto$$d2025-07-27 - 2025-07-31$$gAAIC 25$$wCanada
000283156 245__ $$aRare genetic variants influence regional cortical and subcortical grey matter volumes in genetic frontotemporal dementia: A GENFI Study
000283156 260__ $$c2025
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000283156 520__ $$aThere is substantial heterogeneity in clinical presentation of genetic Frontotemporal Dementia (FTD), even within the same family. This suggests that additional heritability may exist and contribute to this variable presentation. We examined whether gene-based aggregate burden of genome-wide rare variants (minor allele frequency [MAF]: ≤1%) contribute to variation in regional cortical and subcortical grey matter volumes, after controlling for effects of causative mutations in GRN, MAPT, and C9orf72.This study was embedded within the GENetic Frontotemporal dementia Initiative (GENFI), which recruits genetic FTD cases and their asymptomatic at-risk family members, both carriers and non-carriers of FTD mutations. We included 518 participants with genotype (Neurochip; imputed against TOPMed), and T1w-MRI brain volumetric data. Gene-based burden tests that aggregate the number of rare variants by gene were used to examine the association of rare variants (MAF: ≤1%) with regional cortical and subcortical grey matter volumes (70 regions of interest [ROIs]), controlling for age, sex, total intracranial volume, mutation status, scanner site, population stratification, and family membership (kinship matrix) using RVTests. Annotations for loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non-synonymous. Multiple testing correction accounted for the number of genes and number of independent grey matter volumes as calculated by matSpD (p-value threshold: 0.05/(17,053x42) = 6.98 x10-8).Aggregate burden of LOF mutations (DNAJB8-AS1, WDR26, RDM1P5, BSND, CNOT2, DDA1, ASAH2B, PPM1A, HOXD13, ALDH1A1, CENATAC, ANKRD45) was associated with significantly lower volumes within the left temporal lobe (ROIs: left temporal and lateral temporal left), and greater volume in the putamen bilaterally (TSACC). All genes are protein coding, except the DNAJB8-AS1 (antisense RNA) and RDM1P5 (pseudogene), and are variably expressed in the brain. Molecular functions of significant genes involve regulation of gene expression, transcription, and cell cycle, ion channel function, and chromosomal segregation. WDR26 and CNOT2 genes have been implicated in neurodevelopment and neurological disorders respectively; BSND gene is involved in neurotransmission.Identification of deleterious or protective rare variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication in larger cohorts is needed.
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000283156 650_7 $$2NLM Chemicals$$atau Proteins
000283156 650_7 $$2NLM Chemicals$$aC9orf72 Protein
000283156 650_7 $$2NLM Chemicals$$aBiomarkers
000283156 650_7 $$2NLM Chemicals$$aProgranulins
000283156 650_7 $$2NLM Chemicals$$aMAPT protein, human
000283156 650_7 $$2NLM Chemicals$$aC9orf72 protein, human
000283156 650_7 $$2NLM Chemicals$$aGRN protein, human
000283156 650_2 $$2MeSH$$aHumans
000283156 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000283156 650_2 $$2MeSH$$aFrontotemporal Dementia: pathology
000283156 650_2 $$2MeSH$$aFrontotemporal Dementia: diagnostic imaging
000283156 650_2 $$2MeSH$$aMale
000283156 650_2 $$2MeSH$$aFemale
000283156 650_2 $$2MeSH$$aMagnetic Resonance Imaging
000283156 650_2 $$2MeSH$$aMiddle Aged
000283156 650_2 $$2MeSH$$aGray Matter: pathology
000283156 650_2 $$2MeSH$$aGray Matter: diagnostic imaging
000283156 650_2 $$2MeSH$$atau Proteins: genetics
000283156 650_2 $$2MeSH$$aMutation: genetics
000283156 650_2 $$2MeSH$$aC9orf72 Protein: genetics
000283156 650_2 $$2MeSH$$aBiomarkers
000283156 650_2 $$2MeSH$$aProgranulins: genetics
000283156 650_2 $$2MeSH$$aBrain: pathology
000283156 650_2 $$2MeSH$$aBrain: diagnostic imaging
000283156 650_2 $$2MeSH$$aAged
000283156 650_2 $$2MeSH$$aGenome-Wide Association Study
000283156 650_2 $$2MeSH$$aGenotype
000283156 7001_ $$aPasternak, Maurice$$b1
000283156 7001_ $$aPaterson, Andrew D$$b2
000283156 7001_ $$aTartaglia, Carmela$$b3
000283156 7001_ $$aBlack, Sandra E$$b4
000283156 7001_ $$aMitchell, Sara$$b5
000283156 7001_ $$aFreedman, Morris$$b6
000283156 7001_ $$aTang-Wai, David F$$b7
000283156 7001_ $$aRogaeva, Ekaterina$$b8
000283156 7001_ $$aCash, David M$$b9
000283156 7001_ $$aBocchetta, Martina$$b10
000283156 7001_ $$avan Swieten, John$$b11
000283156 7001_ $$aLaforce, Robert$$b12
000283156 7001_ $$aTagliavini, Fabrizio$$b13
000283156 7001_ $$aBorroni, Barbara$$b14
000283156 7001_ $$aGalimberti, Daniela$$b15
000283156 7001_ $$aRowe, James B$$b16
000283156 7001_ $$aGraff, Caroline$$b17
000283156 7001_ $$aFinger, Elizabeth$$b18
000283156 7001_ $$aSorbi, Sandro$$b19
000283156 7001_ $$aMendonca, Alexandre$$b20
000283156 7001_ $$aButler, Christopher R$$b21
000283156 7001_ $$aGerhard, Alexander$$b22
000283156 7001_ $$aSánchez-Valle, Raquel$$b23
000283156 7001_ $$aMoreno, Fermin$$b24
000283156 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b25$$udzne
000283156 7001_ $$aVandenberghe, Rik$$b26
000283156 7001_ $$aDucharme, Simon$$b27
000283156 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b28$$udzne
000283156 7001_ $$aOtto, Markus$$b29
000283156 7001_ $$aSantana, Isabel$$b30
000283156 7001_ $$aRohrer, Jonathan D$$b31
000283156 7001_ $$aMasellis, Mario$$b32
000283156 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz70856_106121$$gVol. 21 Suppl 2, no. S2, p. e106121$$nS2$$pe106121$$tAlzheimer's and dementia$$v21$$x1552-5260$$y2025
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