American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

{"title":"Apples, Oranges, and Biobanks: Ascertainment Bias in Population-Based Studies of Neurodevelopmental Psychiatric Disorders","authors":"Brenda M. Finucane, Scott M. Myers, David H. Ledbetter, Christa Lese Martin, Matthew T. Oetjens","doi":"10.1002/ajmg.b.33034","DOIUrl":"10.1002/ajmg.b.33034","url":null,"abstract":"","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 7","pages":"73-75"},"PeriodicalIF":1.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144176247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Depression Symptom Trajectories in Mothers With the FMR1 Premutation Vary by CGG Repeat Length: A Longitudinal Study of 73 Women Spanning 20–75 Years of Age","authors":"Jessica Klusek,&nbsp;Lauren Jenner,&nbsp;Abigail L. Hogan,&nbsp;Laura Friedman,&nbsp;Elizabeth Berry-Kravis,&nbsp;Flora Tassone,&nbsp;Tatyana Adayev,&nbsp;Amanda J. Fairchild,&nbsp;Jane E. Roberts","doi":"10.1002/ajmg.b.33033","DOIUrl":"10.1002/ajmg.b.33033","url":null,"abstract":"<p>Women with the <i>FMR1</i> premutation (FXpm) are at heightened genetic vulnerability for depression, with risk compounded by the stressors of parenting a disabled child. Although risk factors persist as FXpm women age, depression in FXpm mothers during midlife and old age is poorly characterized. This study used an accelerated longitudinal design to capture the trajectory of depressive symptoms in 73 FXpm mothers across 20–75 years of age. The FXpm mothers had children with fragile X syndrome or FXpm and contributed 2–11 longitudinal assessments, for a total of 294 observations. Mothers with mid-range CGG expansions (91–110 CGG repeats) exhibited the highest overall symptoms, with a marked increase in depression during early midlife, followed by late midlife trajectories that varied by history of premature menopause. Symptoms of mothers with high CGGs (111–200) peaked during early and late adulthood rather than midlife. At low CGGs (55–90) symptoms were low and stable across age. Parenting stress was associated with increased symptoms during early adulthood, but this effect dwindled with age. Findings illuminate evolving patterns of depression vulnerability across adulthood that are shaped by specific environmental and genetic factors, offering insights for personalized medicine to enhance the health of aging FXpm mothers.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 7","pages":"103-119"},"PeriodicalIF":1.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12355380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Polygenic Risk and Symptom Severity Change After Cognitive Behavioral Therapy for Obsessive-Compulsive Disorder","authors":"Julia Bäckman,&nbsp;John Wallert,&nbsp;Matthew Halvorsen,&nbsp;Bjorn Roelstraete,&nbsp;Elles de Schipper,&nbsp;Nora I. Strom,&nbsp;Thorstein Olsen Eide,&nbsp;Kira D. Höffler,&nbsp;Manuel Mattheisen,&nbsp;Bjarne Hansen,&nbsp;Gerd Kvale,&nbsp;Kristen Hagen,&nbsp;Jan Haavik,&nbsp;Nordic OCD and Related Disorders Consortium (NORDiC),&nbsp;David Mataix-Cols,&nbsp;Christian Rück,&nbsp;James J. Crowley","doi":"10.1002/ajmg.b.33026","DOIUrl":"10.1002/ajmg.b.33026","url":null,"abstract":"<p>A large proportion of patients undergoing cognitive behavior therapy (CBT) for obsessive-compulsive disorder (OCD) do not respond sufficiently to treatment. Identifying predictors for change in symptom severity after treatment could inform clinical decision-making, allow for better-tailored interventions, and avoid treatment failure. Prior research on predictors for treatment response has, however, yielded inconsistent findings with limited clinical utility. Here, we investigated the predictive power of nine polygenic risk scores (PRSs) for psychiatric and cognitive traits in 1598 OCD patients (1167 adults and 431 children/adolescents) treated with CBT in Sweden and Norway. We fitted linear mixed models adjusted for age, sex, genotyping batch, and the first five ancestry PCs to estimate associations between PRS and symptom severity change from pre- to post-treatment. The PRS for schizophrenia showed a modestly significant association with symptom change (<i>β</i> = 0.013, <i>p</i> = 0.04, <i>R</i>\u0000 ² = 0.10), indicating that a higher PRS for schizophrenia was associated with a smaller decrease in symptom severity. No other PRS were significantly associated with the outcome. While these results await replication and expansion, current PRS for psychiatric and cognitive phenotypes do not seem to contribute meaningfully to symptom severity change in CBT for OCD.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 5","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Disentangling Differing Relationships Between Internalizing Disorders and Alcohol Use”","authors":"","doi":"10.1002/ajmg.b.33025","DOIUrl":"10.1002/ajmg.b.33025","url":null,"abstract":"<p>Brasher, M. S., A. D. Grotzinger, N. P. Friedman, H. R. Smolker, and L. M. Evans. 2024. “Disentangling Differing Relationships Between Internalizing Disorders and Alcohol Use.” <i>American Journal of Medical Genetics Part B: Neuropsychiatric Genetics</i> 195B: e32975. https://doi.org/10.1002/ajmg.b.32975.</p><p>In the originally published article, dbGaP phs001672 was not acknowledged properly.</p><p>The Acknowledgments section should have included the following: “The authors thank Million Veteran Program (MVP) staff, researchers, and volunteers, who have contributed to MVP, and especially participants who previously served their country in the military and now generously agreed to enroll in the study. (See https://www.research.va.gov/mvp/ for more details). The citation for MVP is Gaziano, J.M. et al. Million Veteran Program: A mega-biobank to study genetic influences on health and disease. J Clin Epidemiol 70, 214–23 (2016). This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by the Veterans Administration (VA) Million Veteran Program (MVP) award #000.”</p><p>The second sentence in the Methods section should read: “Internalizing phenotypes included the generalized anxiety disorder two item questionnaire (GAD-2) score from (Levey et al., 2020, summary statistics available through dbGaP phs001672), a meta-analysis of lifetime anxiety disorder from (Purves et al., 2020), and a meta-analysis of broad depression from (Howard et al., 2018).”</p><p>The Data Availability Statement should have included: “phs001672: Veterans Administration (VA) Million Veteran Program (MVP) Summary Results from Omics Studies.”</p><p>We apologize for this error.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 5","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetic Testing for Predicting Methylphenidate Treatment Outcomes in Childhood Attention Deficit Hyperactivity Disorder in Turkey: Focus on Carboxylesterase 1, Latrophilin-3, and Catechol-O-Methyltransferase","authors":"Ipek Suzer Gamli,&nbsp;Anne Van Veggel,&nbsp;Rabia Sevcan Karaaslan,&nbsp;Ajla Hodzic Kuerec,&nbsp;Zeina Marzoukah,&nbsp;Ibrahim Adak,&nbsp;Gulay Bulut,&nbsp;Huseyin Tunc,&nbsp;Candan Perry Hizel,&nbsp;Cuneyd Parlayan,&nbsp;Ozalp Ekinci,&nbsp;Ron Van Schaik,&nbsp;Demet Akin","doi":"10.1002/ajmg.b.33024","DOIUrl":"10.1002/ajmg.b.33024","url":null,"abstract":"<div>\u0000 \u0000 <p>Pharmacogenetic studies involving Carboxylesterase 1 (CES1), Latrophilin-3 (LPHN3), and Catechol-O-methyltransferase (COMT) revealed individual differences regarding therapeutic response in children with attention deficit hyperactivity disorder (ADHD) under methylphenidate (MPH) treatment. This study aimed to evaluate MPH's association with the adverse effect status in children and its relationship with CES1, LPHN3, and COMT in the Turkish population. The study included 102 children and adolescents with ADHD, who were categorized as responders, or the adverse effect group based on their treatment response. The Naranjo Adverse Drug Reaction Probability Scale evaluated the presence and severity of adverse effects. Saliva sample was taken from the patients and genotype distribution of CES1 rs3815583, CES1 rs2307227, LPHN3 rs6551665, LPHN3 rs1947274, LPHN3 rs6858066, LPHN3 rs2345039, and COMT rs4680 were examined. In the adverse effect group, instances of carrying the GG genotype in CES1 rs2307227, having G vs. T genotype and GG vs. GT were significantly higher. In LPHN3 rs2345039, carrying the C genotype vs. G was associated with a serious adverse effect. In COMT rs4680, individuals with the AA or GG genotype were significantly higher in the adverse effect group. Our study suggests a relationship between genetic polymorphisms and the side effect status in children receiving MPH.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 5","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143045582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RYR3 Variants Are Potentially Associated With Idiopathic (Non-Lesional) Partial Epilepsy/Susceptibility of Seizures, Toward Understanding the Gene-Disease Association by Genetic Dependent Nature","authors":"Yang Tian,&nbsp;Yun-Qi Hou,&nbsp;Qiong-Xiang Zhai,&nbsp;Xing-Wang Song,&nbsp;Bing-Mei Li,&nbsp;Jie Wang,&nbsp;Jing-Jing Ji,&nbsp;Yin-Ting Liao,&nbsp;Wen-Xiong Chen,&nbsp;Bin Li,&nbsp;Wei-Ping Liao","doi":"10.1002/ajmg.b.33023","DOIUrl":"10.1002/ajmg.b.33023","url":null,"abstract":"<div>\u0000 \u0000 <p>The <i>RYR3</i> gene encodes a brain-type ryanodine receptor that functions to release calcium from intracellular storage and plays an essential role in calcium signaling. The associations between <i>RYR3</i> variants and brain disorders remain unknown. We performed whole-exome sequencing in patients with idiopathic (non-lesional) partial epilepsy of unknown etiology. One de novo missense and six biallelic missense <i>RYR3</i> variants were identified in seven unrelated cases. These variants had no or extremely low allele frequencies in the general population and were predicted to alter hydrogen bonds/decrease protein stability. Patients presented with partial seizures or secondarily generalized tonic–clonic seizures. All patients were seizure-free with/without anti-seizure treatment. Four showed antecedent febrile seizures, a typical susceptibility disorder that is related to the precipitating factor of fever. The genetic dependence nature (GDN) of <i>RYR3</i>, which is defined as the distinct impact of the absence of a gene on normal life, is “obligatory” (causing disease phenotypes). Complete abolishing of <i>RYR3</i> results in abnormal phenotypes instead of lethality, whereas partial/mild impairment (usually more common) is associated with mild disease or increased susceptibility to disease, consistent with our findings. <i>RYR3</i> is therefore potentially a candidate disease gene or susceptibility gene for idiopathic partial epilepsy.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 5","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Internalizing Psychiatric Symptoms in People With Mosaicism for Trisomy 21","authors":"Ruth C. Brown,&nbsp;Allison D'Aguilar,&nbsp;Quinn Hurshman,&nbsp;Rebekah NailorZee,&nbsp;Timothy P. York,&nbsp;George Capone,&nbsp;Ananda B. Amstadter,&nbsp;Colleen Jackson-Cook","doi":"10.1002/ajmg.b.33022","DOIUrl":"10.1002/ajmg.b.33022","url":null,"abstract":"<p>People with mosaicism for trisomy 21 have been shown to exhibit many of the same phenotypic traits present in people with non-mosaic Down syndrome, but with varying symptom severity. However, the behavioral phenotype of people with mosaic Down syndrome (mDS) has not been well characterized. This study aimed to examine the prevalence of self-report and caregiver-report symptoms of depression and anxiety among a sample of 62 participants with mDS aged 12–46 and assess their association with the percentage of trisomy 21 in blood and/or buccal mucosa cells. The overall MANCOVA revealed a significant effect of trisomy on the set of internalizing scales, controlling for age and gender (<i>p</i> = 0.038, partial eta² = 0.22). However, follow-up univariate analyses showed that the initial significant effect of trisomy on fear (<i>p</i> = 0.049, partial eta² = 0.08) did not survive correction for multiple comparisons (adjusted <i>p</i> = 0.300). No other effects were significant. This study highlights the high occurrence of depression and anxiety symptoms in individuals with mDS and the need for routine assessment to optimize their care. It also demonstrates the ability of people with mDS to complete these evaluations, thereby supporting their inclusion in research studies/clinical trials.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 5","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appraising the Effects of Gut Microbiota on Insomnia Risk Through Genetic Causal Analysis","authors":"Peihong Li,&nbsp;Song Wang,&nbsp;Jiaxin Li,&nbsp;Zheng Xiao,&nbsp;Haoyue Zhu,&nbsp;Dandan Sheng,&nbsp;Weiping Liu,&nbsp;Bo Xiao,&nbsp;Luo Zhou","doi":"10.1002/ajmg.b.33021","DOIUrl":"10.1002/ajmg.b.33021","url":null,"abstract":"<div>\u0000 \u0000 <p>BackgroundInsomnia is a common neurological disorder that exhibits connections with the gut microbiota; however, the exact causal relationship remains unclear. MethodsWe conducted a Mendelian randomization (MR) study to systematically evaluate the causal effects of genus-level gut microbiota on insomnia risk in individuals of European ancestry. Summary-level datasets on gut microbiota were sourced from the genome-wide association study (GWAS) of MiBioGen, while datasets on insomnia were obtained from the GWAS of Neale Lab and FinnGen. The primary analytical approach used was the inverse-variance weighted (IVW) method, supplemented by MR-Egger, maximum likelihood, MR-robust adjusted profile score, and weighted median. Sensitivity analyses were conducted to ensure robustness. ResultsThe microbial taxa <i>Enterorhabdus</i>, <i>Family XIII AD3011 group</i>, <i>Paraprevotella</i>, and <i>Lachnospiraceae UCG004</i> were associated with an increased risk of insomnia, whereas <i>Coprococcus1</i>, <i>Coprobacter, Desulfovibrio, Flavonifractor, Olsenella, Odoribacter</i>, and <i>Oscillibacter</i> were linked to a decreased risk. Regarding the insomnia phenotype characterized by trouble falling asleep, the microbial taxon <i>Eisenbergiella</i> was correlated with an increased risk, while <i>Haemophilus</i> and the <i>Eubacterium brachy group</i> were associated with a reduced risk. Furthermore, for the insomnia phenotype characterized by waking too early, the microbial taxa <i>Family XIII UCG001</i>, <i>Lachnospiraceae FCS020 group</i>, and <i>Olsenella</i> were linked to an increased risk, whereas the <i>Eubacterium brachy group</i> and <i>Victivallis</i> were associated with a lower risk. The results remained robust across all sensitivity analyses. ConclusionOur MR study identified multiple genus-level gut microbial taxa that may exhibit potential causal effects on insomnia from a genetic perspective. These findings provide evidence supporting the theory of the microbiota-gut-brain axis and offer new insights into potential prevention and therapeutic targets for insomnia.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 4","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Transdiagnostic Childhood Externalizing Pathology Within an Electronic Medical Records Database and Application to the Analysis of Rare Copy Number Variation","authors":"India A. Reddy,&nbsp;Lide Han,&nbsp;Sandra Sanchez-Roige,&nbsp;Maria Niarchou,&nbsp;Douglas M. Ruderfer,&nbsp;Lea K. Davis","doi":"10.1002/ajmg.b.33020","DOIUrl":"10.1002/ajmg.b.33020","url":null,"abstract":"<p>Externalizing traits and behaviors are broadly defined by impairments in self-regulation and impulse control that typically begin in childhood and adolescence. Externalizing behaviors, traits, and symptoms span a range of traditional psychiatric diagnostic categories. In this study, we sought to generate an algorithm that could reliably identify transdiagnostic childhood-onset externalizing cases and controls within a university hospital electronic health record (EHR) database. Within the Vanderbilt University Medical Center (VUMC) EHR, our algorithm identified cases with a clinician-validated positive predictive value of 90% and controls with a negative predictive value of 88%. In individuals of genetically defined European ancestry (CEU-clustered; <i>N</i>_case = 487, <i>N</i>_control = 5638), case status was significantly associated with psychiatric comorbidity and with elevated externalizing polygenic scores (OR: 1.20; 95% CI: 1.09–1.33; <i>p</i> = 1.14 × 10⁻³; based on published genome-wide association data). To test whether our cohort definitions could be applied to generate novel genetic insights, we examined rare (allele frequency &lt; 0.5%) copy number variation. An association (OR: 9.70; CI: 3.24–29.0) was identified in the CEU-clustered cohort on chromosome 2 (chr2: 45,408,678–45,551,530; duplication), although the statistical strength of this association was modest (<i>p</i> = 0.052). We also examined the role of an externalizing burden score based on the number of externalizing diagnoses present in cases and found similar results to our case–control analysis. This analysis identified several other statistically significant CNV region associations. This study provides a framework for identifying childhood externalizing case–control cohorts within an EHR. Future work should validate this framework within other health systems. A broadly applicable algorithm, like this one, may allow for detection of rare outcomes or outcomes in populations historically excluded from genomic research through meta-analysis of data across health care systems.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 4","pages":""},"PeriodicalIF":1.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.33020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meta-Analysis of Transcriptomic Studies of Blood and Six Brain Regions Identifies a Consensus of 15 Cross-Tissue Mechanisms in Alzheimer's Disease and Suggests an Origin of Cross-Study Heterogeneity","authors":"Jiahui Hou,&nbsp;Jonathan L. Hess,&nbsp;Chunling Zhang,&nbsp;Jeroen G. J. van Rooij,&nbsp;Gentry C. Hearn,&nbsp;Chun Chieh Fan,&nbsp;Stephen V. Faraone,&nbsp;Christine Fennema-Notestine,&nbsp;Shu-Ju Lin,&nbsp;Valentina Escott-Price,&nbsp;Sudha Seshadri,&nbsp;the Alzheimer's Disease Neuroimaging Initiative,&nbsp;Peter Holmans,&nbsp;Ming T. Tsuang,&nbsp;William S. Kremen,&nbsp;Chris Gaiteri,&nbsp;Stephen J. Glatt","doi":"10.1002/ajmg.b.33019","DOIUrl":"10.1002/ajmg.b.33019","url":null,"abstract":"<div>\u0000 \u0000 <p>The comprehensive genome-wide nature of transcriptome studies in Alzheimer's disease (AD) should provide a reliable description of disease molecular states. However, the genes and molecular systems nominated by transcriptomic studies do not always overlap. Even when results do align, it is not clear if those observations represent true consensus across many studies. A couple of sources of variation have been proposed to explain this variability, including tissue-of-origin and cohort type, but its basis remains uncertain. To address this variability and extract reliable results, we utilized all publicly available blood or brain transcriptomic datasets of AD, comprised of 24 brain studies with 4007 samples from six different brain regions, and eight blood studies with 1566 samples. We identified a consensus of AD-associated genes across brain regions and AD-associated gene-sets across blood and brain, generalizable machine learning and linear scoring classifiers, and significant contributors to biological diversity in AD datasets. While AD-associated genes did not significantly overlap between blood and brain, our findings highlighted 15 dysregulated processes shared across blood and brain in AD. The top five most significantly dysregulated processes were DNA replication, metabolism of proteins, protein localization, cell cycle, and programmed cell death. Conversely, addressing the discord across studies, we found that large-scale gene co-regulation patterns can account for a significant fraction of variability in AD datasets. Overall, this study ranked and characterized a compilation of genes and molecular systems consistently identified across a large assembly of AD transcriptome studies in blood and brain, providing potential candidate biomarkers and therapeutic targets.</p>\u0000 </div>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"198 4","pages":""},"PeriodicalIF":1.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}