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Background: Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.
Methods: Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.
Results: Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.
Conclusions: In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.
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http://dx.doi.org/10.1016/j.biopsych.2014.09.017 | DOI Listing |
Brain Struct Funct
December 2024
State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
Microglia play important roles in maintaining homeostasis and immunoreactive defense in the central nervous system including retina. To accomplish such a wide range of functions, microglia are highly heterogeneous. Dark microglia (DM) were recently identified by electron microscopy (EM).
View Article and Find Full Text PDFJ Cell Mol Med
December 2024
Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China.
Aortic dissection (AD) represents a critical condition characterised by a tear in the inner lining of the aorta, leading to the leakage of blood into the layers of the aortic wall, posing a significant risk to life. However, the pathogenesis is unclear. In this study, scRNA-seq was applied to cells derived from aortas of both AD and non-AD donors (control) to unveil the cellular landscape.
View Article and Find Full Text PDFOsteoarthr Cartil Open
March 2025
Department of Rheumatology, Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Objective: Neuroimaging investigations are critical to provide a more direct assessment of brain disturbances associated with osteoarthritis (OA)-related pain, and to better understand its pathophysiology to develop new treatment strategies. This viewpoint aims to summarize the importance of the brain in OA pain.
Method: A European working group on pain in osteoarthritis GO-PAIN (Going Inside Osteoarthritis-related Pain Phenotyping) has been created to work on a global assessment of the OA-related pain.
Cell Death Discov
December 2024
Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, Liaoning, People's Republic of China.
Cell plasticity refers to the deviation of cells from normal terminal differentiation states when faced with environmental and genetic toxic stresses, resulting in the phenomenon of transforming into other cell or tissue phenotypes. Unlocking phenotype plasticity has been defined as a hallmark of malignant tumors. The stomach is one of the organs in the body with the highest degree of self-renewal and exhibits significant cell plasticity.
View Article and Find Full Text PDFTransl Psychiatry
December 2024
West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Depression is a heterogeneous and complex psychological syndrome with highly variable manifestations, which poses difficulties for treatment and prognosis. Depression patients are prone to developing various comorbidities, which stem from different pathophysiological mechanisms, remaining largely understudied. The current study focused on identifying comorbidity-specific phenotypes, and whether these clustered phenotypes are associated with different treatment patterns, clinical manifestations, physiological characteristics, and prognosis.
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