Background: Cognition and its two critical proxies, socioeconomic status (SES) and educational attainment (EA), contribute substantially to human health and are heritable. Elucidating the genetic characteristics of SES/EA/Cognition not only helps to understand the innate individual differences in cognition, but also aids in unraveling the biological mechanisms of complex cognitive-related disorders such as Alzheimer's disease (AD). Here, we explored the rare and common protein-coding variants impacting the comprehensive cognition phenotypic spectrum by leveraging large-scale exomes.
Method: Using 350,770 exomes from the UK Biobank, we performed gene-based collapsing analysis and single-variant analysis for rare and common variants, respectively. Identified genes were biological annotated at multiple levels of gene sets, tissue types and cell types. The identified genetic associations with SES/EA/Cognition were further extended to brain structure, blood chemical markers, and neuropsychiatric phenotypes. Lastly, Mendelian randomization (MR) analysis and druggability evaluations were performed to reveal potential therapeutic targets.
Result: We identified 79 SES/EA/Cognition-associated genes (64 novel) after Bonferroni correction, 29 from gene-based collapsing tests for rare variants (P < 2.19 × 10) and 50 from single-variant association analysis for common variants (P < 1.08 × 10). The intersection of rare variants with genome-wide association studies signals prioritized ADGRB2 and KDM5B, and the effect of rare KDM5B variants was independent of nearby common variants. Pathway enrichment analysis revealed the involvement of synapse and hepatic metabolism. Multiple human brain tissue types as well as cell clusters of excitatory neuron and microgila were enriched. Rare variants in five genes (C2CD2L, IGF1R, AKNRD12, GIGYF1, KDM5B) and 35 common variants showed pleiotropy with broader biological phenotypes, including hippocampus volume and neurodegenerative diseases. MR analysis revealed the causal relationships between the expression levels of 23 genes in brain with SES/EA/Cognition (7 mapped to drug targets).
Conclusion: This study utilizes large-scale exome sequencing to provide a more comprehensive genetic framework underlying SES/EA/Cognition, offering informative associated genes and biological insights. The identified 79 genes across full allele frequency spectrum, 64 of which exhibited novel associations, would provide an abundant resource for further in-depth molecular mechanistic studies and drug development for cognition.
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http://dx.doi.org/10.1002/alz.088059 | DOI Listing |
Orphanet J Rare Dis
January 2025
Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan.
Background: Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients.
View Article and Find Full Text PDFActa Neuropathol Commun
January 2025
Department of Biological Sciences, Purdue University, 915 Mitch Daniels Blvd, West Lafayette, IN, USA.
Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer's disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity.
View Article and Find Full Text PDFInt Immunopharmacol
January 2025
Department of Pathology, Xiangya Hospital, Central South University, Changsha City, Hunan Province, China; Department of Pathology, School of Basic Medicine, Central South University, Changsha City, Hunan Province, China; Ultrapathology (Biomedical Electron Microscopy) Center, Department of Pathology, Xiang-ya Hospital, Central South University, Changsha City, Hunan Province, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Xiangya Hospital, Central South University, Changsha City, Hunan Province, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha City, Hunan Province, China; FuRong Laboratory, Changsha City, Hunan Province, China. Electronic address:
Background: Neoadjuvant chemotherapy, particularly the use of platinum-based compounds and taxanes, is pivotal in the treatment of epithelial-derived tumors, such as cervical cancer and esophageal squamous cell carcinoma (ESCC); however, resistance remains a significant challenge. Utilizing Mendelian randomization (MR) with pharmacogenomics offers a novel approach to understanding the genetic underpinnings of drug responses, thereby aiding in personalized treatment.
Methods: Single-cell RNA sequencing (scRNA-seq) analysis revealed a shared cellular subpopulation of CD8 + T effector memory (CD8 + TEM) cells that are pivotal in mediating chemotherapy resistance in ESCC and cervical cancer.
Braz J Otorhinolaryngol
January 2025
Shanghai Jiao Tong University, School of Medicine, Hainan Branch of Shanghai Children's Medical Center, Department of Otorhinolaryngology, Sanya, China; Shanghai Jiao Tong University, School of Medicine, Shanghai Children's Medical Center, Department of Otorhinolaryngology, Shanghai, China. Electronic address:
Objective: We aimed to investigate the correlation between prevalent risk factors for high-risk neonates in neonatal intensive care unit and their hearing loss, and to examine the audiological features and genetic profiles associated with different deafness mutations in our tertiary referral center. This research seeks to deepen our understanding of the etiology behind congenital hearing loss.
Methods: We conducted initial hearing screenings, including automated auditory brainstem response, distortion product otoacoustic emission, and acoustic immittance on 443 high-risk neonates within 7 days after birth and 42 days (if necessary) after birth.
Am J Med Genet C Semin Med Genet
January 2025
Gastrointestinal and Endocrine Tumor Unit, Medical Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
RET gene is a driver of thyroid cancer (TC) tumorigenesis. The incidence of TC has increased worldwide in the last few decades, both in medullary and follicular-derived subtypes. Several drugs, including multikinase and selective inhibitors, have been explored.
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