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...· 0 citations
OBJECTIVES
Pathological ossification leading to spinal ankylosis is a hallmark of ankylosing spondylitis (AS), yet its molecular mechanisms remain poorly understood. We investigated the genetic basis and functional consequences of severe familial AS to identify pathways driving structural progression.
METHODS
Genome-wide linkage analysis and whole-exome sequencing were performed in a multiplex family with severe AS. A heterozygous knock-in mouse carrying the identified EXTL3 variant was generated and characterized using microCT, histology, transcriptomics, primary osteoblast and chondrocyte cultures, and biochemical analyses of heparan sulfate (HS) metabolism.
RESULTS
A rare missense variant in EXTL3, a key enzyme involved in HS biosynthesis, was identified in affected family members. Extl3mut/+ mice developed sacroiliac structural abnormalities, osteoid accumulation and early joint bridging, together with impaired trabecular bone architecture. Mechanistically, the mutation accelerated chondrocyte hypertrophy while delaying osteoblast maturation and mineralization. These changes were associated with activation of Wnt signalling, increased HS accumulation, enhanced heparanase expression and altered glycosaminoglycan homeostasis. Collectively, these findings identify EXTL3-mediated HS dysregulation as a novel mechanism linking abnormal bone remodelling to pathological ossification.
CONCLUSIONS
Our study identifies EXTL3 as a genetic modifier of structural severity in AS and reveals a previously unrecognised role for HS metabolism in pathological ossification. These findings support a model in which HLA-B27 primarily confers disease susceptibility, whereas rare variants such as EXTL3 contribute to structural progression, highlighting HS-related pathways as potential therapeutic targets.
S. Hilliquin, Olivier Fogel, Mathilde Tissier et al.· Annals of the Rheumatic Dise...· 0 citations
The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that the perinatal environment shapes susceptibility to complex traits across life [1]. The placenta, a transient organ mediating maternal-fetal exchange, plays a central role in this process and has emerged as a key molecular archive in utero [2-4]. Placental DNA methylation (DNAm) is a unique mediator between prenatal exposures, fetal genetics and later-life outcomes [5-9]. DNAm quantitative trait loci (mQTL) have helped disentangling causal mechanisms underlying GWAS loci for complex diseases [10-15]. Despite growing evidence that placental genomic regulation has broad and profound effects on the developmental programming of early- and later-life health outcomes [17], existing placental studies remain limited in scale and largely focused on growth- and neuro-related traits [12-16]. Here, we construct a high-resolution placental mQTL resource and systematically investigate how placental DNAm relates to early- and later-life traits, and to shared vulnerability and complex interactions among them.
A. Cilleros-Portet, Itziar González-Moro, Hachem Sadikki et al.· medRxiv· 0 citations