While genetic heritability plays a major role in the development of cognitive impairment, most genetic risk factors are identified from studies of European populations. We conducted a genome-wide association study (GWAS) on cognitive impairment in the Chinese population by sequencing 1,040 matched case-control individuals from a longitudinal cohort of Zhejiang Province, China. We detected 19 SNPs clustered in 15 genomic loci reaching suggestive significance (P < 1 × 10− 5). Eleven of these genomic loci are newly associated with Alzheimer’s disease (AD) or cognitive impairment, among which five (GRP39, FAT1, EDIL3, ZNF596, and PDGFD) show nominal evidence of replication in both external GWAS of AD in East-Asian populations and summary statistics of AD in diverse populations. The detected loci are implicated in micronutrient homeostasis including zinc (GPR39), iron (STEAP1), potassium (KCNJ6), and vitamin K (VKORC1L1), cell connections (EVPLL) through cadherin regulations (PCDH18, FAT1), regulating amyloid-beta precursor protein (APP) (EDIL3), formation of amyloid-β (EDEM1) and neurofibrillary tangles (PDGFD, ZNF596), neuronal growth (NEGR1), and phosphatase regulations (SETBP1, TPTE). This study presents a robust GWAS for cognitive impairment in the Chinese population and highlights a promising set of therapeutic targets for neurodegenerative disorder.
Depression is one of the most common and disabling non-motor symptoms in Parkinson’s disease (PD), yet its genetic basis remains poorly understood. Here, we investigate the genetic contributions to depression in PD by estimating the burden from common as well as low-frequency single nucleotide polymorphisms (SNPs) within genes previously implicated in PD or depression risk among European ancestry PD patients from three population-based studies. Using gene-based association analyses (SKAT, Burden, and SKAT-O) in the PASIDA, PEG, and PPMI studies, we evaluated SNP sets in gene regions previously linked to PD or depression. Among PD-related genes, meta-analysis identified a significant association between KRTCAP2 and self-reported depression diagnosis in PD (SKAT-O p = 4.33 × 10⁻⁵), which remained significant after false discovery rate correction. A higher genetic burden in KRTCAP2 was associated with 20
Constitutional chromosomal heteromorphisms are common cytogenetic variants involving constitutive heterochromatin and acrocentric short-arm structures whose visual identification and classification remain challenging in routine cytogenetic practice. This study evaluated interobserver reliability in the visual classification of constitutional chromosomal heteromorphisms and characterized differences between homologous chromosomes using digital morphometry. A retrospective cross-sectional study included peripheral blood cytogenetic studies performed between 2021 and 2024. Sixty-six cases with previously reported heteromorphisms were included, yielding 73 heteromorphism observations. Four cytogeneticists, blinded to the original classification and clinical information, independently evaluated selected Q-banded metaphases using predefined visual criteria. Interobserver agreement was assessed using Krippendorff’s alpha and Gwet’s AC1. Digital morphometric analysis was performed in Fiji by measuring the chromosomal region associated with each heteromorphism, defined as the target region (TR), and calculating its absolute size and its ratio to total chromosome size (TR/T). Homologous chromosomes were compared using the Wilcoxon signed-rank test. Overall observed agreement was 70.1
Skeletal dysplasias are a diverse group of genetically inherited bone disorders which may manifest with or without short stature. Extreme short stature can also result from different growth hormone deficiencies. Our research aimed to identify the genetic causes of recessively inherited short stature, with or without skeletal abnormalities in Pakistani families. We recruited participants from thirty-eight pedigrees with a history of these disorders. Radiological examinations were performed for a few patients. Some samples were first screened for variants in GHRHR and RMRP by Sanger sequencing. Next, exome sequencing was carried out for selected patients from each family. Exome data were annotated and all were analyzed using Franklin software while some data were also analyzed using the 3billion automated system. Candidate variants were confirmed by segregation analyses in each family. We identified ten novel homozygous variants in AARS2, COL2A1, ERCC6, EVC2, GHR, IHH, MYH3, NPR2, OBSL1 and TG segregating with the phenotypes in ten different families. In-silico analyses predicted these variants to be deleterious to the genes or the encoded proteins. AARS2 variants have not been previously described to cause short stature. Members of the other twenty-five families had variants in nine different genes. A GHRHR founder mutation accounted for short stature without skeletal abnormalities in 12 families. In contrast, significant genetic heterogeneity was observed in the group of families with short stature accompanied by skeletal dysplasia. In conclusion, our study has broadened the genotypic and phenotypic spectrum of multiple genes and the associated diseases with short stature and skeletal dysplasia.
Congenital disorders of glycosylation (CDG) represent a diverse group of inborn errors of metabolism caused by defective glycosylation processes, usually characterized by multiorgan involvement and overlapping clinical symptoms. This study aimed to decipher the clinical and genetic landscape of CDG in Egypt to enumerate the most common CDG types and unveil potentially new candidate genes. The study included 80 patients from 57 families with molecular findings consistent with CDG. Consanguinity was noted in 90
