Pub Date : 2024-08-29DOI: 10.1101/2024.08.29.24312761
Liangying Yin, Menghui Liu, Yujia Shi, Ruoyu Zhang, Simon Sai-Yu Lui, Hon-Cheong So
Psychiatric disorders are highly heterogeneous, and it is clinically meaningful to distinguish psychiatric disorders by the presence or absence of a specific comorbid condition. In this study, we employed a recently developed algorithm (CombGWAS) to decipher the genetic basis of psychiatric disorder combinations. The focus was on comorbidities and combinations of disorders, such as major depressive disorder(MDD) with and without schizophrenia(SCZ), which can be considered as two ‘subtypes’ of MDD. We also studied psychiatric disorders comorbid with obesity as disease subtypes.
{"title":"Uncovering the genetic underpinnings for different psychiatric disorder combinations","authors":"Liangying Yin, Menghui Liu, Yujia Shi, Ruoyu Zhang, Simon Sai-Yu Lui, Hon-Cheong So","doi":"10.1101/2024.08.29.24312761","DOIUrl":"https://doi.org/10.1101/2024.08.29.24312761","url":null,"abstract":"Psychiatric disorders are highly heterogeneous, and it is clinically meaningful to distinguish psychiatric disorders by the presence or absence of a specific comorbid condition. In this study, we employed a recently developed algorithm (CombGWAS) to decipher the genetic basis of psychiatric disorder combinations. The focus was on comorbidities and combinations of disorders, such as major depressive disorder(MDD) with and without schizophrenia(SCZ), which can be considered as two ‘subtypes’ of MDD. We also studied psychiatric disorders comorbid with obesity as disease subtypes.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1101/2024.08.28.24312746
Kaitlin E. Samocha, V. Kartik Chundru, Jack M. Fu, Eugene J. Gardner, Petr Danecek, Emilie M. Wigdor, Daniel S. Malawsky, Sarah J. Lindsay, Patrick Campbell, Tarjinder Singh, Ruth Y. Eberhardt, Giuseppe Gallone, Caroline F. Wright, Hilary C. Martin, Helen V. Firth, Matthew E. Hurles
While the role of de novo and recessively-inherited coding variation in risk for rare developmental disorders (DDs) has been well established, the contribution of damaging variation dominantly-inherited from parents is less explored. Here, we investigated the contribution of rare coding variants to DDs by analyzing 13,452 individuals with DDs, 18,613 of their family members, and 3,943 controls using a combination of family-based and case/control analyses. In line with previous studies of other neuropsychiatric traits, we found a significant burden of rare (allele frequency < 1×10-5) predicted loss-of-function (pLoF) and damaging missense variants, the vast majority of which are inherited from apparently unaffected parents. These predominantly inherited burdens are strongest in DD-associated genes or those intolerant of pLoF variation in the general population, however we estimate that ∼10% of the excess of these variants in DD cases is found within the DD-associated genes, implying many more risk loci are yet to be identified. We found similar, but attenuated, burdens when comparing the unaffected parents of individuals with DDs to controls, indicating that parents have elevated risk of DDs due to these rare variants, which are overtransmitted to their affected children. We estimate that 6-8.5% of the population attributable risk for DDs are due to rare pLoF variants in those genes intolerant of pLoF variation in the general population. Finally, we apply a Bayesian framework to combine evidence from these analyses of rare, mostly-inherited variants with prior de novo mutation burden analyses to highlight an additional 25 candidate DD- associated genes for further follow up.
{"title":"Substantial role of rare inherited variation in individuals with developmental disorders","authors":"Kaitlin E. Samocha, V. Kartik Chundru, Jack M. Fu, Eugene J. Gardner, Petr Danecek, Emilie M. Wigdor, Daniel S. Malawsky, Sarah J. Lindsay, Patrick Campbell, Tarjinder Singh, Ruth Y. Eberhardt, Giuseppe Gallone, Caroline F. Wright, Hilary C. Martin, Helen V. Firth, Matthew E. Hurles","doi":"10.1101/2024.08.28.24312746","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312746","url":null,"abstract":"While the role of <em>de novo</em> and recessively-inherited coding variation in risk for rare developmental disorders (DDs) has been well established, the contribution of damaging variation dominantly-inherited from parents is less explored. Here, we investigated the contribution of rare coding variants to DDs by analyzing 13,452 individuals with DDs, 18,613 of their family members, and 3,943 controls using a combination of family-based and case/control analyses. In line with previous studies of other neuropsychiatric traits, we found a significant burden of rare (allele frequency < 1×10<sup>-5</sup>) predicted loss-of-function (pLoF) and damaging missense variants, the vast majority of which are inherited from apparently unaffected parents. These predominantly inherited burdens are strongest in DD-associated genes or those intolerant of pLoF variation in the general population, however we estimate that ∼10% of the excess of these variants in DD cases is found within the DD-associated genes, implying many more risk loci are yet to be identified. We found similar, but attenuated, burdens when comparing the unaffected parents of individuals with DDs to controls, indicating that parents have elevated risk of DDs due to these rare variants, which are overtransmitted to their affected children. We estimate that 6-8.5% of the population attributable risk for DDs are due to rare pLoF variants in those genes intolerant of pLoF variation in the general population. Finally, we apply a Bayesian framework to combine evidence from these analyses of rare, mostly-inherited variants with prior <em>de novo</em> mutation burden analyses to highlight an additional 25 candidate DD- associated genes for further follow up.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1101/2024.08.28.24312742
Philippos Koulousakis, Rick Reijnders, Inez Ramakers, Frans Verhey, Tim Vanmierlo, Daniël L.A. van den Hove, Renzo J.M. Riemens
Recent studies have highlighted the role of oxytocin (OXT) in Alzheimer’s disease (AD) dementia and demonstrated its potential as a therapeutic target to reverse cognitive impairment and mitigate AD pathology. Epigenetic dysregulation of OXT has been identified in brain tissue from AD patients, and DNA methylation levels of the exact same locus in the blood of healthy aged individuals have shown predictive biomarker value for conversion to AD. Building on these insights, we investigated the DNA methylation status of the OXT promoter in blood in a prospective cohort of consecutive patients from the BioBank Alzheimer Center Limburg (BBACL). This cohort included males and females suffering from subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Our findings revealed that DNA methylation levels of the OXT promoter at baseline predict the conversion from MCI to dementia in female participants. In addition to discovering differences in the OXT promoter related to sex, we also observed alterations associated with aging, alcohol consumption, and smoking. Overall, our findings underscore the implications of OXT and its DNA methylation changes in blood within the context of dementia.
最近的研究强调了催产素（OXT）在阿尔茨海默病（AD）痴呆症中的作用，并证明它有可能成为逆转认知障碍和减轻 AD 病理的治疗靶点。在阿尔茨海默病患者的脑组织中发现了 OXT 的表观遗传失调，而健康老年人血液中完全相同位点的 DNA 甲基化水平也显示了其对转化为阿尔茨海默病的预测性生物标志物价值。基于这些认识，我们在林堡生物银行阿尔茨海默病中心（BBACL）的前瞻性连续患者队列中调查了血液中 OXT 启动子的 DNA 甲基化状态。该队列包括患有主观认知能力下降（SCD）、轻度认知障碍（MCI）和痴呆症的男性和女性患者。我们的研究结果表明，基线 OXT 启动子的 DNA 甲基化水平可预测女性参与者从 MCI 向痴呆症的转化。除了发现 OXT 启动子与性别有关的差异外，我们还观察到与衰老、饮酒和吸烟有关的改变。总之，我们的研究结果强调了血液中的 OXT 及其 DNA 甲基化变化对痴呆症的影响。
{"title":"Blood DNA methylation levels of the oxytocin promoter predict conversion from mild cognitive impairment to dementia in females within a clinical cohort of cognitive complaints","authors":"Philippos Koulousakis, Rick Reijnders, Inez Ramakers, Frans Verhey, Tim Vanmierlo, Daniël L.A. van den Hove, Renzo J.M. Riemens","doi":"10.1101/2024.08.28.24312742","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312742","url":null,"abstract":"Recent studies have highlighted the role of oxytocin (OXT) in Alzheimer’s disease (AD) dementia and demonstrated its potential as a therapeutic target to reverse cognitive impairment and mitigate AD pathology. Epigenetic dysregulation of <em>OXT</em> has been identified in brain tissue from AD patients, and DNA methylation levels of the exact same locus in the blood of healthy aged individuals have shown predictive biomarker value for conversion to AD. Building on these insights, we investigated the DNA methylation status of the <em>OXT</em> promoter in blood in a prospective cohort of consecutive patients from the BioBank Alzheimer Center Limburg (BBACL). This cohort included males and females suffering from subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Our findings revealed that DNA methylation levels of the <em>OXT</em> promoter at baseline predict the conversion from MCI to dementia in female participants. In addition to discovering differences in the <em>OXT</em> promoter related to sex, we also observed alterations associated with aging, alcohol consumption, and smoking. Overall, our findings underscore the implications of <em>OXT</em> and its DNA methylation changes in blood within the context of dementia.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.27.24312158
Matthew Jensen, Corrine Smolen, Anastasia Tyryshkina, Lucilla Pizzo, Deepro Banerjee, Matthew Oetjens, Hermela Shimelis, Cora Taylor, Vijay Kumar Pounraja, Hyebin Song, Laura Rohan, Emily Huber, Laila El Khattabi, Ingrid van de Laar, Rafik Tadros, Connie Bezzina, Marjon van Slegtenhorst, Janneke Kammeraad, Paolo Prontera, Jean-Hubert Caberg, Harry Fraser, Siddhartha Banka, Anke Van Dijck, Charles Schwartz, Els Voorhoeve, Patrick Callier, Anne-Laure Mosca-Boidron, Nathalie Marle, Mathilde Lefebvre, Kate Pope, Penny Snell, Amber Boys, Paul J. Lockhart, Myla Ashfaq, Elizabeth McCready, Margaret Nowacyzk, Lucia Castiglia, Ornella Galesi, Emanuela Avola, Teresa Mattina, Marco Fichera, Maria Grazia Bruccheri, Giuseppa Maria Luana Mandara, Francesca Mari, Flavia Privitera, Ilaria Longo, Aurora Curro, Alessandra Renieri, Boris Keren, Perrine Charles, Silvestre Cuinat, Mathilde Nizon, Olivier Pichon, Claire Beneteau, Radka Stoeva, Dominique Martin-Coignard, Sophia Blesson, Cedric Le Caignec, Sandra Mercier, Marie Vincent, Christa Martin, Katrin Mannik, Alexandre Reymond, Laurence Faivre, Erik Sistermans, R. Frank Kooy, David Amor, Corrado Romano, Joris Andreiux, Santhosh Girirajan
Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion and CHD8 variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.
{"title":"Genetic modifiers and ascertainment drive variable expressivity of complex disorders","authors":"Matthew Jensen, Corrine Smolen, Anastasia Tyryshkina, Lucilla Pizzo, Deepro Banerjee, Matthew Oetjens, Hermela Shimelis, Cora Taylor, Vijay Kumar Pounraja, Hyebin Song, Laura Rohan, Emily Huber, Laila El Khattabi, Ingrid van de Laar, Rafik Tadros, Connie Bezzina, Marjon van Slegtenhorst, Janneke Kammeraad, Paolo Prontera, Jean-Hubert Caberg, Harry Fraser, Siddhartha Banka, Anke Van Dijck, Charles Schwartz, Els Voorhoeve, Patrick Callier, Anne-Laure Mosca-Boidron, Nathalie Marle, Mathilde Lefebvre, Kate Pope, Penny Snell, Amber Boys, Paul J. Lockhart, Myla Ashfaq, Elizabeth McCready, Margaret Nowacyzk, Lucia Castiglia, Ornella Galesi, Emanuela Avola, Teresa Mattina, Marco Fichera, Maria Grazia Bruccheri, Giuseppa Maria Luana Mandara, Francesca Mari, Flavia Privitera, Ilaria Longo, Aurora Curro, Alessandra Renieri, Boris Keren, Perrine Charles, Silvestre Cuinat, Mathilde Nizon, Olivier Pichon, Claire Beneteau, Radka Stoeva, Dominique Martin-Coignard, Sophia Blesson, Cedric Le Caignec, Sandra Mercier, Marie Vincent, Christa Martin, Katrin Mannik, Alexandre Reymond, Laurence Faivre, Erik Sistermans, R. Frank Kooy, David Amor, Corrado Romano, Joris Andreiux, Santhosh Girirajan","doi":"10.1101/2024.08.27.24312158","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312158","url":null,"abstract":"Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion and CHD8 variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"60 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.27.24312374
Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen L Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor
Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in who we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role for COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role for the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.
{"title":"COA5 has an essential role in the early stage of mitochondrial complex IV assembly","authors":"Jia Xin Tang, Alfredo Cabrera-Orefice, Jana Meisterknecht, Lucie Taylor, Geoffray Monteuuis, Maria Ekman Stensland, Adam Szczepanek, Karen L Stals, James Davison, Langping He, Sila Hopton, Tuula A Nyman, Christopher B Jackson, Angela Pyle, Monika Winter, Ilka Wittig, Robert W Taylor","doi":"10.1101/2024.08.27.24312374","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312374","url":null,"abstract":"Pathogenic variants in cytochrome c oxidase assembly factor 5 (COA5), a proposed complex IV (CIV) assembly factor, have been shown to cause clinical mitochondrial disease with two siblings affected by neonatal hypertrophic cardiomyopathy manifesting a rare, homozygous COA5 missense variant (NM_001008215.3: c.157G>C, p.Ala53Pro). The most striking observation in the affected individuals was an isolated impairment in the early stage of mitochondrial CIV assembly. In this study, we report an unrelated family in who we have identified the same COA5 variant with patient-derived fibroblasts and skeletal muscle biopsies replicating an isolated CIV deficiency. A CRISPR/Cas9-edited homozygous COA5 knockout U2OS cell line with similar biochemical profile was generated to interrogate the functional role of the human COA5 protein. Mitochondrial complexome profiling pinpointed a role for COA5 in early CIV assembly, more specifically, its involvement in the stage between MTCO1 maturation and the incorporation of MTCO2. We therefore propose that the COA5 protein plays an essential role for the biogenesis of MTCO2 and its integration into the early CIV assembly intermediate for downstream assembly of the functional holocomplex.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.27.24311855
Noah C. Helderman, Marieke E. IJsselsteijn, Madalina Cabuta, Manon van der Ploeg, Tom van Wezel, Aysel Ahadova, Matthias Kloor, Hans Morreau, Maartje Nielsen, Noel F.C.C. de Miranda
Background and aims: Colorectal carcinomas (CRCs) in patients with Lynch syndrome (LS) exhibit heightened immunogenicity due to mismatch repair deficiency (MMR-d), often resulting in favorable responses to T cell immune checkpoint therapies. Recent studies indicate that the phenotype and genotype of LS-associated CRCs vary depending on the specific MMR gene mutated. Here, we investigated whether the immune profiles of LS-associated CRCs differ based on the MMR gene defects. Methods: Tissue material from 18 MLH1-, 16 MSH2-, 40 MSH6-, and 23 PMS2-mutated CRCs and 35 sporadic MMR-d CRCs were included in the study. Imaging mass cytometry (IMC) analysis, along with targeted multiplex immunofluorescence imaging (mIF) and immunohistochemistry, were applied to examine the tumor immune microenvironment, including Human Leukocyte Antigen (HLA) class I and programmed death-ligand 1 (PD-L1) expression. Results: Unsupervised hierarchical clustering of cell phenotypes identified by IMC, followed by mIF validation, revealed comparable lymphoid and myeloid cell infiltration levels across CRCs from all MMR groups. Infiltrating T cell levels negatively correlated with the number of mutations at coding microsatellite sequences, particularly in MLH1-mutated CRCs. HLA class I defects were observed in 76% of all CRCs. These defects were more frequently accompanied by β2M defects in hereditary MMR-d CRCs (67%) compared to sporadic MMR-d CRCs (37%), and did not associate with the number of γδ T cells, which were present in CRCs from all MMR groups. PD-L1 expression in tumor cells was only detected in 8% of all CRCs. Conclusion: Our findings illustrate that, from an immunological perspective, there is no evidence of differing immunogenic features across MMR defects. This is important to consider when developing preventive vaccine strategies and evaluating immunotherapy for LS patients and those with MMR-d CRCs.
{"title":"Immunological profiles in Lynch syndrome colorectal cancers are not specific to mismatch repair gene defects","authors":"Noah C. Helderman, Marieke E. IJsselsteijn, Madalina Cabuta, Manon van der Ploeg, Tom van Wezel, Aysel Ahadova, Matthias Kloor, Hans Morreau, Maartje Nielsen, Noel F.C.C. de Miranda","doi":"10.1101/2024.08.27.24311855","DOIUrl":"https://doi.org/10.1101/2024.08.27.24311855","url":null,"abstract":"<strong>Background and aims</strong>: Colorectal carcinomas (CRCs) in patients with Lynch syndrome (LS) exhibit heightened immunogenicity due to mismatch repair deficiency (MMR-d), often resulting in favorable responses to T cell immune checkpoint therapies. Recent studies indicate that the phenotype and genotype of LS-associated CRCs vary depending on the specific MMR gene mutated. Here, we investigated whether the immune profiles of LS-associated CRCs differ based on the MMR gene defects. <strong>Methods</strong>: Tissue material from 18 <em>MLH1</em>-, 16 <em>MSH2</em>-, 40 <em>MSH6</em>-, and 23 <em>PMS2</em>-mutated CRCs and 35 sporadic MMR-d CRCs were included in the study. Imaging mass cytometry (IMC) analysis, along with targeted multiplex immunofluorescence imaging (mIF) and immunohistochemistry, were applied to examine the tumor immune microenvironment, including Human Leukocyte Antigen (HLA) class I and programmed death-ligand 1 (PD-L1) expression. <strong>Results</strong>: Unsupervised hierarchical clustering of cell phenotypes identified by IMC, followed by mIF validation, revealed comparable lymphoid and myeloid cell infiltration levels across CRCs from all MMR groups. Infiltrating T cell levels negatively correlated with the number of mutations at coding microsatellite sequences, particularly in <em>MLH1</em>-mutated CRCs. HLA class I defects were observed in 76% of all CRCs. These defects were more frequently accompanied by β2M defects in hereditary MMR-d CRCs (67%) compared to sporadic MMR-d CRCs (37%), and did not associate with the number of γδ T cells, which were present in CRCs from all MMR groups. PD-L1 expression in tumor cells was only detected in 8% of all CRCs. <strong>Conclusion</strong>: Our findings illustrate that, from an immunological perspective, there is no evidence of differing immunogenic features across MMR defects. This is important to consider when developing preventive vaccine strategies and evaluating immunotherapy for LS patients and those with MMR-d CRCs.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.25.24312540
Qian Gong, Honggang Lyu, Lijun Kang, Simeng Ma, Nan Zhang, Xin-hui Xie, Enqi Zhou, Zipeng Deng, Jiewei Liu, Zhongchun Liu
Post-traumatic stress disorder (PTSD) may be linked to abnormalities in neural circuits that facilitate fear learning and memory processes. The precise degree to which this connection is influenced by genetic factors is still uncertain. This study aimed to investigate the genetic association between PTSD and its corresponding brain circuitry components. We conducted a meta-analysis using the summary of PTSD genome-wide association studies (GWAS) from multiple cohorts to enhance statistical power (sample size = 306,400). Based on the result, and utilizing the lifetime trauma events (LTE) trait as a control for PTSD, we investigated the genetic association of PTSD and LTE with 9 brain structure traits related to the brain circuitry (4 cortical, 2 subcortical, and 3 white matter) by various methodologies, including heritability tissue enrichment analysis, global and local genetic correlations, polygenic overlap analysis, and causal inference. As a result, we discovered the enrichment of heritability for PTSD within circuitry-relevant brain regions such as the cingulate cortex and frontal cortex, and we identified genetic correlations between PTSD and these brain regions. We have observed a polygenic overlap and a total of 31 novel jointly significant genetic loci (conjunction FDR < 0.05). These loci are involved in the process of DNA damage and repair as well as the pathway of neurodegenerative diseases. We also identified a potential causal relationship between PTSD and the surface area of the frontal pole. Our findings offer a valuable understanding of the genetic mechanisms underlying PTSD and its associated brain circuitry.
创伤后应激障碍（PTSD）可能与促进恐惧学习和记忆过程的神经回路异常有关。这种联系受遗传因素影响的确切程度仍不确定。本研究旨在调查创伤后应激障碍与相应脑回路成分之间的遗传关联。我们利用多个队列的创伤后应激障碍全基因组关联研究（GWAS）摘要进行了一项荟萃分析，以提高统计效力（样本量=306,400）。在此基础上，我们利用终生创伤事件（LTE）特质作为创伤后应激障碍的对照，通过遗传率组织富集分析、整体和局部遗传相关性、多基因重叠分析和因果推断等多种方法，研究了创伤后应激障碍和LTE与大脑回路相关的9个大脑结构特质（4个皮质、2个皮质下和3个白质）的遗传相关性。结果，我们发现创伤后应激障碍的遗传率在扣带回皮层和额叶皮层等与电路相关的脑区富集，并确定了创伤后应激障碍与这些脑区之间的遗传相关性。我们观察到了多基因重叠现象，共发现了 31 个新的联合显著遗传位点（联合 FDR < 0.05）。这些基因位点涉及 DNA 损伤和修复过程以及神经退行性疾病的发病途径。我们还发现了创伤后应激障碍与额极表面积之间的潜在因果关系。我们的研究结果为了解创伤后应激障碍及其相关脑回路的遗传机制提供了宝贵的信息。
{"title":"The Genetic Relationships Between Post-Traumatic Stress Disorder and Its Corresponding Neural Circuit Structures","authors":"Qian Gong, Honggang Lyu, Lijun Kang, Simeng Ma, Nan Zhang, Xin-hui Xie, Enqi Zhou, Zipeng Deng, Jiewei Liu, Zhongchun Liu","doi":"10.1101/2024.08.25.24312540","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312540","url":null,"abstract":"Post-traumatic stress disorder (PTSD) may be linked to abnormalities in neural circuits that facilitate fear learning and memory processes. The precise degree to which this connection is influenced by genetic factors is still uncertain. This study aimed to investigate the genetic association between PTSD and its corresponding brain circuitry components. We conducted a meta-analysis using the summary of PTSD genome-wide association studies (GWAS) from multiple cohorts to enhance statistical power (sample size = 306,400). Based on the result, and utilizing the lifetime trauma events (LTE) trait as a control for PTSD, we investigated the genetic association of PTSD and LTE with 9 brain structure traits related to the brain circuitry (4 cortical, 2 subcortical, and 3 white matter) by various methodologies, including heritability tissue enrichment analysis, global and local genetic correlations, polygenic overlap analysis, and causal inference. As a result, we discovered the enrichment of heritability for PTSD within circuitry-relevant brain regions such as the cingulate cortex and frontal cortex, and we identified genetic correlations between PTSD and these brain regions. We have observed a polygenic overlap and a total of 31 novel jointly significant genetic loci (conjunction FDR < 0.05). These loci are involved in the process of DNA damage and repair as well as the pathway of neurodegenerative diseases. We also identified a potential causal relationship between PTSD and the surface area of the frontal pole. Our findings offer a valuable understanding of the genetic mechanisms underlying PTSD and its associated brain circuitry.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.25.24312255
Connor J Lewis, Zeynep Vardar, Anna Luisa Kühn, Jean M Johnston, Precilla D'Souza, William A Gahl, Mohammed Salman Shazeeb, Cynthia J Tifft, Maria T Acosta
GM1 gangliosidosis is an ultra-rare inherited neurodegenerative lysosomal storage disorder caused by biallelic mutations in the GLB1 gene. GM1 is uniformly fatal and has no approved therapies, although clinical trials investigating gene therapy as a potential treatment for this condition are underway. Novel outcome measures or biomarkers demonstrating the longitudinal effects of GM1 and potential recovery due to therapeutic intervention are urgently needed to establish efficacy of potential therapeutics. One promising tool is differential tractography, a novel imaging modality utilizing serial diffusion weighted imaging (DWI) to quantify longitudinal changes in white matter microstructure. In this study, we present the novel use of differential tractography in quantifying the progression of GM1 alongside age-matched neurotypical controls. We analyzed 113 DWI scans from 16 GM1 patients and 32 age-matched neurotypical controls to investigate longitudinal changes in white matter pathology. GM1 patients showed white matter degradation evident by both the number and size of fiber tract loss. In contrast, neurotypical controls showed longitudinal white matter improvements as evident by both the number and size of fiber tract growth. We also corroborated these findings by documenting significant correlations between cognitive global impression (CGI) scores of clinical presentations and our differential tractography derived metrics in our GM1 cohort. Specifically, GM1 patients who lost more neuronal fiber tracts also had a worse clinical presentation. This result demonstrates the importance of differential tractography as an important biomarker for disease progression in GM1 patients with potential extension to other neurodegenerative diseases and therapeutic intervention.
{"title":"Differential Tractography: A Biomarker for Neuronal Function in Neurodegenerative Disease","authors":"Connor J Lewis, Zeynep Vardar, Anna Luisa Kühn, Jean M Johnston, Precilla D'Souza, William A Gahl, Mohammed Salman Shazeeb, Cynthia J Tifft, Maria T Acosta","doi":"10.1101/2024.08.25.24312255","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312255","url":null,"abstract":"GM1 gangliosidosis is an ultra-rare inherited neurodegenerative lysosomal storage disorder caused by biallelic mutations in the <em>GLB1</em> gene. GM1 is uniformly fatal and has no approved therapies, although clinical trials investigating gene therapy as a potential treatment for this condition are underway. Novel outcome measures or biomarkers demonstrating the longitudinal effects of GM1 and potential recovery due to therapeutic intervention are urgently needed to establish efficacy of potential therapeutics. One promising tool is differential tractography, a novel imaging modality utilizing serial diffusion weighted imaging (DWI) to quantify longitudinal changes in white matter microstructure. In this study, we present the novel use of differential tractography in quantifying the progression of GM1 alongside age-matched neurotypical controls. We analyzed 113 DWI scans from 16 GM1 patients and 32 age-matched neurotypical controls to investigate longitudinal changes in white matter pathology. GM1 patients showed white matter degradation evident by both the number and size of fiber tract loss. In contrast, neurotypical controls showed longitudinal white matter improvements as evident by both the number and size of fiber tract growth. We also corroborated these findings by documenting significant correlations between cognitive global impression (CGI) scores of clinical presentations and our differential tractography derived metrics in our GM1 cohort. Specifically, GM1 patients who lost more neuronal fiber tracts also had a worse clinical presentation. This result demonstrates the importance of differential tractography as an important biomarker for disease progression in GM1 patients with potential extension to other neurodegenerative diseases and therapeutic intervention.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.25.24312539
Bradley Roberts, Zahra Cooper, Georgia Landery, Susanne Stanley, Bernadette T Majda, Khan RL Collins, P Anthony Akkari, Sean D Hood, Jennifer Rodger
The field of pharmacogenetics (PGx) is experiencing significant growth, with increasing evidence to support its application in psychiatric care, suggesting its potential to personalise treatment plans, optimise medication efficacy, and reduce adverse drug reactions. However, the perceived utility and practicability of PGx for psychiatric treatment in youth remains underexplored. This study investigated youth-perceived barriers and attitudes towards the implementation of PGx testing to guide antidepressant treatment in primary care. Semi-structured focus groups and interviews were conducted with 17 participants aged between 18 to 24 years. These sessions were recorded and transcribed before thematic analysis was used to identify collective themes. Three key themes were identified, including attitudes towards the medication prescription process, concerns and attitudes towards PGx testing, and perceived barriers to its clinical implementation. Although PGx testing was positively perceived by most participants, all participants shared concerns about PGx testing. Participants voiced concerns about the financial impact of PGx testing, the potential for treatment delays, and the accuracy of PGx testing in guiding antidepressant treatment. Additionally, participants noted that the low awareness and willingness of general practitioners to incorporate PGx testing into routine practice could hinder successful clinical implementation. Prior to the implementation of PGx testing into Australian primary practices, it is essential to acknowledge patient perspectives and ensure that clinical practices remain patient-focused. This study highlights important considerations for integrating PGx testing into antidepressant pharmacotherapy and emphasizes the need for future research to address and mitigate youth-perceived barriers.
{"title":"Exploring Youth-Perceived Barriers and Attitudes Towards the Clinical Use of Pharmacogenetic Testing to Optimise Antidepressant Pharmacotherapy","authors":"Bradley Roberts, Zahra Cooper, Georgia Landery, Susanne Stanley, Bernadette T Majda, Khan RL Collins, P Anthony Akkari, Sean D Hood, Jennifer Rodger","doi":"10.1101/2024.08.25.24312539","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312539","url":null,"abstract":"The field of pharmacogenetics (PGx) is experiencing significant growth, with increasing evidence to support its application in psychiatric care, suggesting its potential to personalise treatment plans, optimise medication efficacy, and reduce adverse drug reactions. However, the perceived utility and practicability of PGx for psychiatric treatment in youth remains underexplored. This study investigated youth-perceived barriers and attitudes towards the implementation of PGx testing to guide antidepressant treatment in primary care. Semi-structured focus groups and interviews were conducted with 17 participants aged between 18 to 24 years. These sessions were recorded and transcribed before thematic analysis was used to identify collective themes. Three key themes were identified, including attitudes towards the medication prescription process, concerns and attitudes towards PGx testing, and perceived barriers to its clinical implementation. Although PGx testing was positively perceived by most participants, all participants shared concerns about PGx testing. Participants voiced concerns about the financial impact of PGx testing, the potential for treatment delays, and the accuracy of PGx testing in guiding antidepressant treatment. Additionally, participants noted that the low awareness and willingness of general practitioners to incorporate PGx testing into routine practice could hinder successful clinical implementation. Prior to the implementation of PGx testing into Australian primary practices, it is essential to acknowledge patient perspectives and ensure that clinical practices remain patient-focused. This study highlights important considerations for integrating PGx testing into antidepressant pharmacotherapy and emphasizes the need for future research to address and mitigate youth-perceived barriers.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.26.24312584
Jonathan Mak, Chenxi Qin, Anna Kuukka, FinnGen Consortium, Sara Hagg, Jake K. L. Lin, Juulia Jylhava
Frailty is a clinically relevant phenotype with significant gaps in our understanding of its etiology. We performed a genome-wide association study of frailty in FinnGen (N=500,737) and replicated the signals in the UK Biobank (N=429,463) using polygenic risk scores (PRSs). We prioritized genes through proteomics integration (N~45,000; UK Biobank) and colocalization of protein quantitative trait loci. Frailty was measured using the Hospital Frailty Risk Score (HFRS). We observed 1,588 variants associated with frailty (p<5x10-8) of which 1,242 were novel, i.e., previously unreported for any trait. The associations mapped to 106 genes of which 31 were novel. PRS replication validated the signals (β=0.074, p<2x10-16). Cell type enrichment analysis indicated expression in neuronal cells. Protein levels of KHK, CGREF1, MET, ATXN2, ALDH2, NECTIN2, APOC1, APOE and FOSB were associated with HFRS, whereas colocalized signals were observed within APOE and BRAP. Our results reveal novel genetic contributions and causal candidate genes for frailty.
{"title":"Large-scale genome-wide analyses with proteomics integration reveal novel loci and biological insights into frailty","authors":"Jonathan Mak, Chenxi Qin, Anna Kuukka, FinnGen Consortium, Sara Hagg, Jake K. L. Lin, Juulia Jylhava","doi":"10.1101/2024.08.26.24312584","DOIUrl":"https://doi.org/10.1101/2024.08.26.24312584","url":null,"abstract":"Frailty is a clinically relevant phenotype with significant gaps in our understanding of its etiology. We performed a genome-wide association study of frailty in FinnGen (N=500,737) and replicated the signals in the UK Biobank (N=429,463) using polygenic risk scores (PRSs). We prioritized genes through proteomics integration (N~45,000; UK Biobank) and colocalization of protein quantitative trait loci. Frailty was measured using the Hospital Frailty Risk Score (HFRS). We observed 1,588 variants associated with frailty (p<5x10-8) of which 1,242 were novel, i.e., previously unreported for any trait. The associations mapped to 106 genes of which 31 were novel. PRS replication validated the signals (β=0.074, p<2x10-16). Cell type enrichment analysis indicated expression in neuronal cells. Protein levels of KHK, CGREF1, MET, ATXN2, ALDH2, NECTIN2, APOC1, APOE and FOSB were associated with HFRS, whereas colocalized signals were observed within APOE and BRAP. Our results reveal novel genetic contributions and causal candidate genes for frailty.","PeriodicalId":501375,"journal":{"name":"medRxiv - Genetic and Genomic Medicine","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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