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Aging, the greatest risk factor for Alzheimer's disease (AD), may lead to the accumulation of somatic mutations in neurons. We investigated whether somatic mutations, specifically in longer genes, are implicated in AD etiology. First, we modeled the theoretical likelihood of genes being affected by aging‐induced somatic mutations, dependent on their length. We then tested this model and found that long genes are indeed more affected by somatic mutations and that their expression is more frequently reduced in AD brains. Furthermore, using gene‐set enrichment analysis, we investigated the potential consequences of such long gene disruption. We found that long genes are involved in synaptic adhesion and other synaptic pathways that are predicted to be inhibited in the brains of AD patients. Taken together, our findings indicate that long gene–dependent synaptic impairment may contribute to AD pathogenesis. [ABSTRACT FROM AUTHOR]

Molecular mechanisms underlying Alzheimer's disease (AD) are difficult to investigate, partly because diagnosis lags behind the insidious pathological processes. Therefore, identifying AD neuroimaging markers and their genetic modifiers may help study early mechanisms of neurodegeneration. We aimed to identify brain regions of the highest vulnerability to AD using a data‐driven search in the AD Neuroimaging Initiative (ADNI, n = 1,100 subjects), and further explored genetic variants affecting this critical brain trait using both ADNI and the younger UK Biobank cohort (n = 8,428 subjects). Tensor‐Based Morphometry (TBM) and Independent Component Analysis (ICA) identified the limbic system and its interconnecting white‐matter as the most AD‐vulnerable brain feature. Whole‐genome analysis revealed a common variant in SHARPIN that was associated with this imaging feature (rs34173062, p = 2.1 × 10−10). This genetic association was validated in the UK Biobank, where it was correlated with entorhinal cortical thickness bilaterally (p =.002 left and p = 8.6 × 10−4 right), and with parental history of AD (p = 2.3 × 10−6). Our findings suggest that neuroanatomical variation in the limbic system and AD risk are associated with a novel variant in SHARPIN. The role of this postsynaptic density gene product in β1‐integrin adhesion is in line with the amyloid precursor protein (APP) intracellular signaling pathway and the recent genome‐wide evidence. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of neuropsychiatric disorders and highlighted their complexity. Careful consideration of the polygenicity and complex genetic architecture could aid in the understanding of the underlying brain mechanisms. We introduce an innovative approach to polygenic scoring, utilizing imaging-derived phenotypes (IDPs) to predict a clinical phenotype. We leveraged IDP GWAS data from the UK Biobank, to create polygenic imaging-derived scores (PIDSs). As a proof-of-concept, we assessed genetic variations in brain structure between individuals with ADHD and unaffected controls across three NeuroIMAGE waves (n = 954). Out of the 94 PIDS, 72 exhibited significant associations with their corresponding IDPs in an independent sample. Notably, several global measures, including cerebellum white matter, cerebellum cortex, and cerebral white matter, displayed substantial variance explained for their respective IDPs, ranging from 3% to 5.7%. Conversely, the associations between each IDP and the clinical ADHD phenotype were relatively weak. These findings highlight the growing power of GWAS in structural neuroimaging traits, enabling the construction of polygenic scores that accurately reflect the underlying polygenic architecture. However, to establish robust connections between PIDS and behavioral or clinical traits such as ADHD, larger samples are needed. Our novel approach to polygenic risk scoring offers a valuable tool for researchers in the field of psychiatric genetics., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Aging, the greatest risk factor for Alzheimer's disease (AD), may lead to the accumulation of somatic mutations in neurons. We investigated whether somatic mutations, specifically in longer genes, are implicated in AD etiology. First, we modeled the theoretical likelihood of genes being affected by aging-induced somatic mutations, dependent on their length. We then tested this model and found that long genes are indeed more affected by somatic mutations and that their expression is more frequently reduced in AD brains. Furthermore, using gene-set enrichment analysis, we investigated the potential consequences of such long gene disruption. We found that long genes are involved in synaptic adhesion and other synaptic pathways that are predicted to be inhibited in the brains of AD patients. Taken together, our findings indicate that long gene-dependent synaptic impairment may contribute to AD pathogenesis., (© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)