Effective treatments targeting disease etiology are urgently needed for Alzheimer’s disease (AD). Although candidate AD genes have been identified and altering their levels may serve as therapeutic strategies, the consequence of such alterations remain largely unknown. Herein, we analyzed CRISPR knockout/RNAi knockdown screen data for over 700 cell lines and evaluated cellular dependencies of 104 AD-associated genes previously identified by genome-wide association studies (GWAS) and gene expression network studies. Multiple genes showed widespread cell dependencies across tissue lineages, suggesting their inhibition may yield off-target effects. Meanwhile, several genes including SPI1, MEF2C, GAB2, ABCC11, ATCG1 were identified as genes of interest since their genetic knockouts specifically affected high-expressing cells whose tissue lineages are relevant to cell types found in AD. Overall, analyses of genetic screen data identified AD-associated genes whose knockout or knockdown selectively affected cell lines of relevant tissue lineages, prioritizing targets for potential AD treatments.
Background The Hermansky–Pudlak syndrome (HPS) is a genetically heterogeneous group of diseases characterized by oculocutaneous albinism, bleeding diathesis, and systemic complications. It is the most common genetic disorder in Puerto Rico. These patients are at a significant risk of developing a variety of skin complications and little is known about the prevalence of dermatologic diagnoses in this population. Objectives To report dermatologic manifestations in patients with Hermansky–Pudlak syndrome (HPS). Secondary aims include skin concerns, sun protection habits, barriers to dermatologic care, and skin cancer knowledge. Methods Cross-sectional study with twenty-nine Puerto Rican patients who carried a clinical diagnosis of HPS type 1 or type 3 through a telephonic questionnaire. Results Twenty-nine patients participated with a mean (SD) age of 37.3 (16.8) years and the majority were female (69%). The most common diagnoses were skin cancer (34.5%), acne (34.5%), bacterial skin infections (34.5%), warts (24%), urticaria (17.2%), and psoriasis (17.2%). The most common skin concerns were dry skin (62.1%), hair loss (58.9%), redness (34.5%), moles (31%), and rash (31%). The most common sun protection behavior was wearing a shirt that covers the shoulders (93.1%, often or always) and the least common was wearing a hat (24.1%, often or always). Higher income was significantly associated with being more likely to use sunscreen often or always (OR = 3.38, 95% CI 1.02–11.18, p = 0.04). Those in northern urban areas were significantly less likely to report barriers to dermatologic care (OR = 0.13, 95% CI 0.02–0.76, p = 0.02). Conclusions This study provides an important overview of the most common self-reported skin manifestations in patients with HPS. Unfortunately, a high prevalence of cutaneous malignancy was reported. The results stress the need for adequate care and potential interventions to promote sun protection behaviors and skin cancer prevention.
Background Genes involved in the progression of Alzheimer’s disease (AD) have been identified, but these genes have not been studied in the context of CRISPR knockouts and RNAi screens to reveal cell‐specific vulnerabilities. Method A list of 105 AD‐associated genes, found through genome‐wide association studies (GWAS) and gene expression network analyses, was compiled. Expression and knock‐down/out dependency data for over 700 cell lines was obtained through the Cancer Dependency Map (DepMap). The expression‐associated dependencies were specifically examined in three tissue types that may be relevant to AD etiology: hematopoietic and lymphoid tissue, central nervous system, and autonomic ganglia. Result SPI1, MEF2C, GAB2, and ABCC11 in hematopoietic and lymphoid tissue cell lines were established as genes of interest since their genetic knockouts specifically affected cells showing high expression of these genes. Other genes exhibiting expression‐associated dependencies include ACTG1 in autonomic ganglia and GLS in central nervous system cell lines. Investigating these genes for expression and dependency patterns in their respective AD tissue of interest highlighted cell lines that had the most significant decrease in cell survival and growth after CRISPR knockout or RNAi screen. Conclusion SPI1, MEF2C, GAB2, and ABCC11 demonstrated expression‐associated dependencies in cell lines of AD‐associated tissues, and present as potential targets for AD.
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