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@INPROCEEDINGS{Mirza:283156,
      author       = {Mirza, Saira S and Pasternak, Maurice and Paterson, Andrew
                      D and Tartaglia, Carmela and Black, Sandra E and Mitchell,
                      Sara and Freedman, Morris and Tang-Wai, David F and Rogaeva,
                      Ekaterina and Cash, David M and Bocchetta, Martina and van
                      Swieten, John and Laforce, Robert and Tagliavini, Fabrizio
                      and Borroni, Barbara and Galimberti, Daniela and Rowe, James
                      B and Graff, Caroline and Finger, Elizabeth and Sorbi,
                      Sandro and Mendonca, Alexandre and Butler, Christopher R and
                      Gerhard, Alexander and Sánchez-Valle, Raquel and Moreno,
                      Fermin and Synofzik, Matthis and Vandenberghe, Rik and
                      Ducharme, Simon and Levin, Johannes and Otto, Markus and
                      Santana, Isabel and Rohrer, Jonathan D and Masellis, Mario},
      title        = {{R}are genetic variants influence regional cortical and
                      subcortical grey matter volumes in genetic frontotemporal
                      dementia: {A} {GENFI} {S}tudy},
      journal      = {Alzheimer's and dementia},
      volume       = {21},
      number       = {S2},
      issn         = {1552-5260},
      reportid     = {DZNE-2026-00052},
      pages        = {e106121},
      year         = {2025},
      abstract     = {There 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.},
      month         = {Jul},
      date          = {2025-07-27},
      organization  = {Alzheimer’s Association
                       International Conference, Toronto
                       (Canada), 27 Jul 2025 - 31 Jul 2025},
      keywords     = {Humans / Frontotemporal Dementia: genetics / Frontotemporal
                      Dementia: pathology / Frontotemporal Dementia: diagnostic
                      imaging / Male / Female / Magnetic Resonance Imaging /
                      Middle Aged / Gray Matter: pathology / Gray Matter:
                      diagnostic imaging / tau Proteins: genetics / Mutation:
                      genetics / C9orf72 Protein: genetics / Biomarkers /
                      Progranulins: genetics / Brain: pathology / Brain:
                      diagnostic imaging / Aged / Genome-Wide Association Study /
                      Genotype / tau Proteins (NLM Chemicals) / C9orf72 Protein
                      (NLM Chemicals) / Biomarkers (NLM Chemicals) / Progranulins
                      (NLM Chemicals) / MAPT protein, human (NLM Chemicals) /
                      C9orf72 protein, human (NLM Chemicals) / GRN protein, human
                      (NLM Chemicals)},
      cin          = {AG Gasser},
      ddc          = {610},
      cid          = {I:(DE-2719)1210000},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)1 / PUB:(DE-HGF)16},
      pubmed       = {pmid:41505495},
      doi          = {10.1002/alz70856_106121},
      url          = {https://pub.dzne.de/record/283156},
}