White matter hyperintensities (WMH), a key MRI-marker of cerebral small vessel disease (cSVD), are common in older adults and associated with an increased risk of stroke and dementia. The latest WMH genome-wide association study (GWAS) identified 27 loci involving genes enriched for extracellular matrix, myelination, and membrane transport. Genetically predicted WMH correlates with white matter microstructural alterations in young adults and shows causal effects on stroke and dementia. However, biological pathways underlying WMH and their contribution to clinical outcomes remain unclear, and validated polygenic risk scores (PRS) for WMH are lacking. We applied global and pathway-specific PRS (ps-PRS) to generate robust WMH-PRS and identify biological pathways contributing to WMH across the lifespan. We leveraged the largest European-ancestry WMH-GWAS (N=46,944) and data from 15,320 UK Biobank participants with MRI (UKB-MRI) (mean age=67 (7.7) years) to optimize a WMH global-PRS and construct 3,794 ps-PRS based on canonical pathways from the Molecular Signatures Database (v2023.2). The best WMH global-PRS in UKB-MRI (P=1.78 x e-193; delta-R-squared=+4.1%) predicted WMH in independent cohorts: young adults (i-Share, N=1,578, age=22(2.3); P=0.0024; delta-R-squared=+0.5%), older community-dwellers (Three City-Dijon, N=1,443, age=73 (4.1); P=1.38xe-9; delta-R-squared=+2.2%), and memory-clinic patients (Memento, N=1,831, age=71 (8.5); P=1.11xe-19; delta-R-squared=+3.3%). In the UK Biobank (N up to 355,180), WMH global-PRS was associated with incident stroke (HR=1.06 [1.038, 1.082], P=2.6xe-8), including both ischemic stroke (HR=1.061[1.037, 1.086], P=1.6xe-8) and intracerebral hemorrhage (HR=1.083[1.026, 1.143], P=0.004). Higher global-PRS was also associated with incident all-cause dementia (HR=1.051 [1.030, 1.080], P=1xe-5) and its vascular or mixed dementia sub-type (HR=1.168[1.103, 1.237], P=1.1xe-7), but showed no association with Alzheimer's disease. Permutation-based pathway enrichment, performed in UKB-MRI, identified 127 ps-PRS consistently enriched for WMH and clustering into ten biological domains. Of these, 61 ps-PRS (six clusters and 55 individual pathways) were enriched in at least one follow-up cohort: 14 in older community-persons, 17 in young adults, and 37 in memory-clinic patients. Secondary analyses highlighted four ps-PRS involved in lipid metabolism, ciliogenesis, and signal transduction enriched in both young and older adults and associated with stroke and dementia. In the memory-clinic some ps-PRS, notably involved in sphingolipid metabolism, were also associated with dementia. Seven ps-PRS, mostly lipid-related, showed evidence of modulation by hypertension. In summary, we generated a validated WMH global-PRS showing robust association with cSVD clinical complications and introduce a multi-cohort WMH ps-PRS framework that reveals candidate biological pathways with differential associations across the lifespan and clinical outcomes. These findings may inform precision prevention and drug development for cSVD.
T. D'Aoust, A. Tsuchida, C. Dufouil et al.· medRxiv· 0 citations
We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.
Audrey Coulon, F. Rabiller, M. Takalo et al.· Nature Genetics· 0 citations
Copy-number variants (CNVs) are major contributors to human disease. In Alzheimer disease (AD), APP duplications cause autosomal-dominant forms, but the role of CNVs in non-monogenic AD remains poorly characterized. We analyzed rare CNVs (frequency <1%) from 22,319 exomes (4,150 early-onset AD [EOAD, ≤65 years], 8,519 late-onset AD [LOAD], 9,650 unaffected control subjects) using harmonized calling and quality control. After identifying 17 individuals with a pathogenic CNV, we performed exome-wide and gene-set burden analyses. EOAD-affected individuals showed increased burdens of rare CNVs affecting coding genes, particularly deletions in AD-related genes. Integrated loss-of-function (LoF) analysis gathering short truncating variants with deletions showed that ABCA1 (odds ratio [OR] = 5.77 [95% confidence interval 2.25; 17.06], p = 0.0002) and ABCA7 deletions contribute to this deletion burden (OR = 2.29 [1.44; 3.65], p = 0.0006), while CTSB LoF alleles appear as candidates (OR = 5.03 [1.50; 20.71], p = 0.0089). We then performed exome-wide gene-level dosage analysis and highlighted 18 genes across five loci with a false discovery rate of <10%, including the 22q11.21 central region, where deletions were restricted to EOAD (including one de novo event) and duplications were enriched in control individuals, with intermediate frequencies in LOAD. We narrowed this locus to the SCARF2-KLHL22-MED15 region after integrating short truncating variants. Replication in 33,977 affected individuals and 362,322 control subjects confirmed association for 22q11.21 dosage with exome-wide significance (ORSCARF2 = 0.34 [0.21; 0.53]; mega-p value = 5.52 × 10-7). SCARF2 overexpression significantly increased amyloid-β uptake, congruent with duplication-associated decreased AD risk. We conclude that rare coding CNVs in a proportion of AD-associated genes and 22q11.21 deletions, including some found in DiGeorge syndrome, increase AD risk. Conversely, we identify 22q11.21 duplication as a strong AD-risk-decreasing factor.
O. Quenez, Catherine Schramm, K. Cassinari et al.· American Journal of Human Ge...· 1 citation
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