Publications by authors named "Mark Lathrop"
Article Synopsis
- 4-cresol, a substance linked to health benefits in diabetes, enhances insulin sensitivity in mouse myoblasts and boosts insulin secretion in isolated mouse islets.
- The compound demonstrates minimal off-target effects and binds primarily to specific kinases like RPS6KA3, which are important in pancreatic islet function.
- Research indicates that 4-cresol may improve glycemic control and β-cell activity, highlighting its potential role in diabetes treatment.
Article Synopsis
- Lung carcinoids (L-CDs) are rare neuroendocrine tumors more common in women and categorized into typical (TCs) and atypical carcinoids (ACs), with ACs having worse prognosis.
- A study of 15 L-CDs revealed two distinct subtypes, L-CD-PanC, likened to pancreatic tumors, and L-CD-NeU, akin to neuroendocrine tumors, differentiated by their genetic and epigenetic profiles.
- L-CD-PanC tumors showed changes related to metabolic and pancreatic genes, while L-CD-NeU tumors exhibited high mutational loads and specific environmental mutational signatures, suggesting different underlying causes and potential treatment implications.
Purpose: Genetic susceptibility to nonsyndromic renal cell carcinoma (RCC) remains poorly understood, especially for different histological subtypes, as does variations in genetic predisposition in different populations. The objectives of this study were to identify risk genes for RCC in the Canadian population, investigate their clinical significance, and evaluate variations in germline pathogenic variants (PVs) among patients with RCC across the globe.
Materials And Methods: We conducted targeted sequencing of 19 RCC-related and 27 cancer predisposition genes for 960 patients with RCC from Canada and identified genes enriched in rare germline PVs in RCC compared with cancer-free controls.
Article Synopsis
- Cerebral small vessel disease (cSVD) is a major contributor to stroke and dementia, and currently lacks specific treatments, prompting a study using Mendelian randomization to identify protein associations.
- The research combined cerebrospinal fluid (CSF) and plasma data with genetic studies to identify 49 proteins linked to cSVD, highlighting 16 that appeared in both fluids and showing connections to immune response and extracellular matrix pathways.
- Notably, many identified proteins were associated with stroke and dementia, with some already having known drug targets, paving the way for potential new biomarkers and therapies for cSVD.
Article Synopsis
- - The age at diagnosis of Type 1 diabetes (T1D) is influenced by both the age at which autoimmune damage begins and the speed at which beta cells are destroyed, with genetics playing a key role, particularly in children.
- - A study of European children diagnosed with T1D from 1980-2008 identified 14 specific SNPs (genetic variants) associated with age at diagnosis, including new associations not found in previous studies.
- - Many of the identified genetic loci are linked to immune system functions and other autoimmune conditions, indicating that these genes may significantly contribute to the early immune processes leading to beta cell destruction in T1D.
Article Synopsis
- Cerebral small vessel disease (cSVD) is a significant contributor to stroke and dementia, predominantly indicated by white matter hyperintensities (WMH) seen in MRI scans of older adults.
- Recent research has linked genetic risk factors for WMH to the microstructure of white matter in young adults, which suggests that early changes in the brain's structure may be relevant to cSVD.
- A study involving genome-wide association testing identified 21 genetic loci related to neurite density and orientation in young adults, showcasing potential early markers for understanding cSVD's progression and underlying mechanisms.
Coronary artery disease (CAD), the most prevalent cardiovascular disease, is the leading cause of death worldwide. Heritable factors play a significant role in the pathogenesis of CAD. It has been proposed that approximately one-third of patients with CAD have a positive family history, and individuals with such history are at ~1.
View Article and Find Full Text PDFIdentifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.
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- The study investigates how vascular risk factors like blood pressure, diabetes, and body mass index relate to the risk and recurrence of cervical artery dissections (CeADs), a major cause of stroke in young people.
- Using genetic analysis, it found that higher systolic and diastolic blood pressure significantly increases the risk of CeAD, while higher body mass index showed unclear effects.
- The research suggests that β-blockers could lower the risk of CeAD, which could help shape prevention strategies and clinical trials related to this condition.
Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.
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- The study aims to uncover new genetic factors linked to calcific aortic stenosis (AS) and identify mechanisms through functional and expression data integration.
- A large genome-wide meta-analysis involving over 653,000 European participants found 17 significant genetic loci associated with AS, with further support for their involvement from independent cohorts.
- Findings highlight the roles of dyslipidemia, inflammation, calcification, and obesity in AS development, suggesting potential new strategies for treatment and prevention.
Article Synopsis
- A study investigated the role of tumor genomics in predicting recurrence risk for patients with localized clear-cell renal cell carcinoma (ccRCC) after surgery, using a large cohort of 943 cases.
- Researchers analyzed the mutation status of 12 genes, particularly focusing on von-Hippel Lindau (VHL) mutations, finding distinct groups with different disease-free survival rates.
- The results suggest that genomic profiling can help tailor adjuvant treatment decisions, with patients having only a VHL mutation possibly needing less aggressive therapy compared to those with additional mutations.
Article Synopsis
- * This study analyzed rare genetic variants by combining data from 21 cohorts worldwide, involving over 5,000 severe cases and 571,000 controls.
- * A significant finding showed that a rare harmful variant in the TLR7 gene greatly increases the risk of severe COVID-19, indicating that rare variants could offer valuable insights for understanding and treating the disease.
Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.
View Article and Find Full Text PDFBackground: Recombinant human growth hormone (rhGH) has shown a great growth-promoting potential in children with idiopathic short stature (ISS). However, the response to rhGH differs across individuals, largely due to genetic and epigenetic heterogeneity. Since epigenetic marks on the methylome can be dynamically influenced by GH, we performed a comprehensive pharmacoepigenomics analysis of DNA methylation changes associated with long-term rhGH administration in children with ISS.
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- - Cerebral small vessel disease is a major factor in strokes and cognitive decline, but specific genetic causes are not well understood; this study explores genetic links using data from large cohorts of older individuals with MRI scans and genetic profiles.
- - The researchers found significant associations with extreme small vessel disease at 11 genomic loci; notably, a new association was identified at chr12q24.11, and common variants in the EFEMP1 and TRIM47 genes were linked to disease severity.
- - The study suggests that the severity of small vessel disease is causally associated with higher risks for stroke and Alzheimer's; TRIM47, in particular, plays a crucial role in brain vascular health and is enriched in brain endothelial cells.
Purpose: The Canadian Longitudinal Study on Aging (CLSA) Comprehensive cohort was established to provide unique opportunities to study the genetic and environmental contributions to human disease as well as ageing process. The aim of this report was to describe the genomic data included in CLSA.
Participants: A total of 26 622 individuals from the CLSA Comprehensive cohort of men and women aged 45-85 recruited between 2010 and 2015 underwent genome-wide genotyping of DNA samples collected from blood.
Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.
View Article and Find Full Text PDFChronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation.
View Article and Find Full Text PDFBackground: Québec was the Canadian province most impacted by COVID-19, with 401,462 cases as of September 24th, 2021, and 11,347 deaths due mostly to a very severe first pandemic wave. In April 2020, we assembled the Coronavirus Sequencing in Québec (CoVSeQ) consortium to sequence SARS-CoV-2 genomes in Québec to track viral introduction events and transmission within the province.
Methods: Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec.
Genomic Studies Across the Lifespan Point to Early Mechanisms Determining Subcortical Volumes.
Biol Psychiatry Cogn Neurosci Neuroimaging
June 2022
Article Synopsis
- Subcortical brain structures are crucial in age-related neurodegenerative disorders, and early-life factors, including genetic influences, may affect their development and risk of later-life neurological diseases.
- The study analyzed large population-based brain imaging data to estimate heritability of subcortical volumes across different age groups and investigated genetic associations with these volumes.
- Findings revealed that heritability of subcortical volumes decreases with age, with certain genetic loci linked to smaller volumes in both older and younger adults, suggesting a genetic connection to cognitive performance and Alzheimer's risk.*
Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.
View Article and Find Full Text PDFBackground: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal fibrotic interstitial lung disease. Few circulating biomarkers have been identified to have causal effects on IPF.
Methods: To identify candidate IPF-influencing circulating proteins, we undertook an efficient screen of circulating proteins by applying a two-sample Mendelian randomisation (MR) approach with existing publicly available data.