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@ARTICLE{LeGrand:270140,
      author       = {Le Grand, Quentin and Tsuchida, Ami and Koch, Alexandra and
                      Imtiaz, Mohammed Aslam and Aziz, N Ahmad and Vigneron,
                      Chloé and Zago, Laure and Lathrop, Mark and Dubrac,
                      Alexandre and Couffinhal, Thierry and Crivello, Fabrice and
                      Matthews, Paul M and Mishra, Aniket and Breteler, Monique M
                      B and Tzourio, Christophe and Debette, Stéphanie},
      title        = {{D}iffusion imaging genomics provides novel insight into
                      early mechanisms of cerebral small vessel disease.},
      journal      = {Molecular psychiatry},
      volume       = {29},
      number       = {11},
      issn         = {1359-4184},
      address      = {London},
      publisher    = {Macmillan},
      reportid     = {DZNE-2024-00740},
      pages        = {3567 - 3579},
      year         = {2024},
      abstract     = {Cerebral small vessel disease (cSVD) is a leading cause of
                      stroke and dementia. Genetic risk loci for white matter
                      hyperintensities (WMH), the most common MRI-marker of cSVD
                      in older age, were recently shown to be significantly
                      associated with white matter (WM) microstructure on
                      diffusion tensor imaging (signal-based) in young adults. To
                      provide new insights into these early changes in WM
                      microstructure and their relation with cSVD, we sought to
                      explore the genetic underpinnings of cutting-edge
                      tissue-based diffusion imaging markers across the adult
                      lifespan. We conducted a genome-wide association study of
                      neurite orientation dispersion and density imaging (NODDI)
                      markers in young adults (i-Share study: N = 1 758,
                      (mean[range]) 22.1[18-35] years), with follow-up in young
                      middle-aged (Rhineland Study: N = 714, 35.2[30-40] years)
                      and late middle-aged to older individuals (UK Biobank: N =
                      33 224, 64.3[45-82] years). We identified 21 loci associated
                      with NODDI markers across brain regions in young adults. The
                      most robust association, replicated in both follow-up
                      cohorts, was with Neurite Density Index (NDI) at chr5q14.3,
                      a known WMH locus in VCAN. Two additional loci were
                      replicated in UK Biobank, at chr17q21.2 with NDI, and
                      chr19q13.12 with Orientation Dispersion Index (ODI).
                      Transcriptome-wide association studies showed associations
                      of STAT3 expression in arterial and adipose tissue
                      (chr17q21.2) with NDI, and of several genes at chr19q13.12
                      with ODI. Genetic susceptibility to larger WMH volume, but
                      not to vascular risk factors, was significantly associated
                      with decreased NDI in young adults, especially in regions
                      known to harbor WMH in older age. Individually, seven of 25
                      known WMH risk loci were associated with NDI in young
                      adults. In conclusion, we identified multiple novel genetic
                      risk loci associated with NODDI markers, particularly NDI,
                      in early adulthood. These point to possible early-life
                      mechanisms underlying cSVD and to processes involving
                      remyelination, neurodevelopment and neurodegeneration, with
                      a potential for novel approaches to prevention.},
      keywords     = {Humans / Cerebral Small Vessel Diseases: genetics /
                      Genome-Wide Association Study: methods / Female / Male /
                      Adult / Middle Aged / Aged / Diffusion Tensor Imaging:
                      methods / White Matter: diagnostic imaging / White Matter:
                      metabolism / Brain: metabolism / Young Adult / Aged, 80 and
                      over / Genomics: methods / Adolescent / Diffusion Magnetic
                      Resonance Imaging: methods / Polymorphism, Single
                      Nucleotide: genetics / Neurites: metabolism},
      cin          = {AG Breteler / AG Aziz},
      ddc          = {610},
      cid          = {I:(DE-2719)1012001 / I:(DE-2719)5000071},
      pnm          = {354 - Disease Prevention and Healthy Aging (POF4-354)},
      pid          = {G:(DE-HGF)POF4-354},
      experiment   = {EXP:(DE-2719)Rhineland Study-20190321},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11541005},
      pubmed       = {pmid:38811690},
      doi          = {10.1038/s41380-024-02604-7},
      url          = {https://pub.dzne.de/record/270140},
}