Genetic risk factors underlying white matter hyperintensities and cortical atrophy
Yash Patel
(1, 2)
,
Jean Shin
(1, 2)
,
Eeva Sliz
(3)
,
Ariana Tang
(1, 2)
,
Aniket Mishra
(4)
,
Rui Xia
(5)
,
Edith Hofer
(6, 7)
,
Hema Sekhar Reddy Rajula
(4)
,
Ruiqi Wang
(8)
,
Frauke Beyer
(4, 9)
,
Katrin Horn
(10)
,
Max Riedl
(10)
,
Jing Yu
(11)
,
Henry Völzke
(12)
,
Robin Bülow
(12)
,
Uwe Völker
(12)
,
Stefan Frenzel
(12)
,
Katharina Wittfeld
(12)
,
Sandra van der Auwera
(12, 13)
,
Thomas H Mosley
(14)
,
Vincent Bouteloup
(4, 15, 16)
,
Jean-Charles Lambert
(17, 18)
,
Genevieve Chene
(4, 15)
,
Carole Dufouil
(4)
,
Christophe Tzourio
(4, 15)
,
Jean-François Mangin
(19, 20)
,
Rebecca F Gottesman
(21)
,
Myriam Fornage
(5)
,
Reinhold Schmidt
(7)
,
Qiong Yang
(8)
,
Veronica Witte
(9)
,
Markus Scholz
(10)
,
Markus Loeffler
(10)
,
Gennady V Roshchupkin
(22)
,
M Arfan Ikram
(22)
,
Hans J Grabe
(12)
,
Sudha Seshadri
(23)
,
Stephanie Debette
(4, 15)
,
Tomas Paus
(24, 25, 26)
,
Zdenka Pausova
(1, 2, 25, 24)
1
SickKids -
The Hospital for sick children [Toronto]
2 University of Toronto
3 University of Oulu
4 BPH - Bordeaux population health
5 UTHealth - The University of Texas Health Science Center at Houston
6 IMI - Institut für Medizinische Informatik, Statistik und Dokumentation [Graz]
7 Medical University of Graz = Medizinische Universität Graz
8 Boston University School of Public Health
9 IMPNSC - Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig]
10 Leipzig University / Universität Leipzig
11 Erasmus MC Cancer Institute, Rotterdam
12 University of Medicine Greifswald
13 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
14 UMMC - University of Mississippi Medical Center
15 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
16 CIC Bordeaux
17 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
18 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
19 NEUROSPIN - Service NEUROSPIN
20 BAOBAB - Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields
21 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
22 Erasmus MC - Erasmus University Medical Center [Rotterdam]
23 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
24 UQAM - Université du Québec à Montréal = University of Québec in Montréal
25 CHU Sainte Justine [Montréal]
26 McGill University = Université McGill [Montréal, Canada]
2 University of Toronto
3 University of Oulu
4 BPH - Bordeaux population health
5 UTHealth - The University of Texas Health Science Center at Houston
6 IMI - Institut für Medizinische Informatik, Statistik und Dokumentation [Graz]
7 Medical University of Graz = Medizinische Universität Graz
8 Boston University School of Public Health
9 IMPNSC - Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig]
10 Leipzig University / Universität Leipzig
11 Erasmus MC Cancer Institute, Rotterdam
12 University of Medicine Greifswald
13 DZNE - German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen
14 UMMC - University of Mississippi Medical Center
15 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
16 CIC Bordeaux
17 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
18 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
19 NEUROSPIN - Service NEUROSPIN
20 BAOBAB - Building large instruments for neuroimaging: from population imaging to ultra-high magnetic fields
21 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
22 Erasmus MC - Erasmus University Medical Center [Rotterdam]
23 IMN - Institut des Maladies Neurodégénératives [Bordeaux]
24 UQAM - Université du Québec à Montréal = University of Québec in Montréal
25 CHU Sainte Justine [Montréal]
26 McGill University = Université McGill [Montréal, Canada]
Résumé
White matter hyperintensities index structural abnormalities in the cerebral white matter, including axonal damage. The latter may promote atrophy of the cerebral cortex, a key feature of dementia. Here, we report a study of 51,065 individuals from 10 cohorts demonstrating that higher white matter hyperintensity volume associates with lower cortical thickness. The meta-GWAS of white matter hyperintensities-associated cortical 'atrophy' identifies 20 genome-wide significant loci, and enrichment in genes specific to vascular cell types, astrocytes, and oligodendrocytes. White matter hyperintensities-associated cortical 'atrophy' showed positive genetic correlations with vascular-risk traits and plasma biomarkers of neurodegeneration, and negative genetic correlations with cognitive functioning. 15 of the 20 loci regulated the expression of 54 genes in the cerebral cortex that, together with their co-expressed genes, were enriched in biological processes of axonal cytoskeleton and intracellular transport. The white matter hyperintensities-cortical thickness associations were most pronounced in cortical regions with higher expression of genes specific to excitatory neurons with long-range axons traversing through the white matter. The meta-GWAS-based polygenic risk score predicts vascular and all-cause dementia in an independent sample of 500,348 individuals. Thus, the genetics of white matter hyperintensities-related cortical atrophy involves vascular and neuronal processes and increases dementia risk.
Domaines
Santé publique et épidémiologie| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
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