Biology subjects

Montgomery, S. B.

Publications and source records attributed to Montgomery, S. B..

6 recordsLinked to original sources

bioRxiv2018

Ocular disease mechanisms elucidated by genetics of human fetal retinal pigment epithelium gene expression

The eye is an intricate organ with limited representation in large-scale functional genomics datasets. The retinal pigment epithelium (RPE) serves vital roles in ocular development and retinal homeostasis. We interrogated the genetics of gene expression of cultured human fetal RPE (fRPE) cells under two metabolic conditions. Genes with disproportionately high fRPE expression are enriched for genes related to inherited ocular diseases. Variants near these fRPE-selective genes explain a larger fraction of risk for both age-related macular degeneration (AMD) and myopia than variants near genes enriched in 53 other human tissues. Increased mitochondrial oxidation of glutamine by fRPE promoted expression of lipid synthesis genes implicated in AMD. Expression and splice quantitative trait loci (e/sQTL) analysis revealed shared and metabolic condition-specific loci of each type and several eQTL not previously described in any tissue. Fine mapping of fRPE e/sQTL across AMD and myopia genome-wide association data suggests new candidate genes, and mechanisms by which the same common variant of RDH5 contributes to both increased AMD risk and decreased myopia risk. Our study highlights the unique transcriptomic characteristics of fRPE and provides a resource to connect e/sQTL in a critical ocular cell type to monogenic and complex eye disorders.

genomics↗

bioRxiv2018

Identification of rare-disease genes in diverse undiagnosed cases using whole blood transcriptome sequencing and large control cohorts

RNA sequencing (RNA-seq) is a complementary approach for Mendelian disease diagnosis for patients in whom exome-sequencing is not informative. For both rare neuromuscular and mitochondrial disorders, its application has improved diagnostic rates. However, the generalizability of this approach to diverse Mendelian diseases has yet to be evaluated. We sequenced whole blood RNA from 56 cases with undiagnosed rare diseases spanning 11 diverse disease categories to evaluate the general application of RNA-seq to Mendelian disease diagnosis. We developed a robust approach to compare rare disease cases to existing large sets of RNA-seq controls (N=1,594 external and N=31 family-based controls) and demonstrated the substantial impacts of gene and variant filtering strategies on disease gene identification when combined with RNA-seq. Across our cohort, we observed that RNA-seq yields a 8.5% diagnostic rate. These diagnoses included diseases where blood would not intuitively reflect evidence of disease. We identified RARS2 as an under-expression outlier containing compound heterozygous pathogenic variants for an individual exhibiting profound global developmental delay, seizures, microcephaly, hypotonia, and progressive scoliosis. We also identified a new splicing junction in KCTD7 for an individual with global developmental delay, loss of milestones, tremors and seizures. Our study provides a broad evaluation of blood RNA-seq for the diagnosis of rare disease.

genomics↗

bioRxiv2018

Genetic analyses in UK Biobank identifies 78 novel loci associated with urinary biomarkers providing new insights into the biology of kidney function and chronic disease

BackgroundUrine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases.\n\nMethodsWe performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium, and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank, a large population-based cohort study of over 500,000 individuals recruited across the United Kingdom in 2006-2010. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers.\n\nResultsWe identified 23 genome-wide significant independent loci associated with creatinine, 20 for microalbumin, 12 for potassium, and 38 for sodium. We confirmed several established associations including between the CUBN locus and microalbumin (rs141640975, p=3.11e-68). Variants associated with the levels of urinary creatinine, potassium, and sodium mapped to loci previously associated with obesity (GIPR, rs1800437, p=9.81e-10), caffeine metabolism (CYP1A1, rs2472297, p=1.61e-8) and triglycerides (GCKR, rs1260326, p=4.37e-16), respectively. We detected high pairwise genetic correlation between the levels of four urinary biomarkers, and significant genetic correlation between their levels and several anthropometric, cardiovascular, glycemic, lipid and kidney traits. We highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium.\n\nConclusionWe report 78 novel genome-wide significant associations with urinary levels of creatinine, microalbumin, potassium and sodium in the UK Biobank, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases.\n\nAuthor SummaryUrine biomarkers, such as creatinine, microalbumin, potassium and sodium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease and diabetes mellitus. Knowledge about the genetic determinants of the levels of these biomarker may shed light on pathophysiological mechanisms underlying the development of these diseases. Here, we performed genome-wide association studies of urinary levels of creatinine, microalbumin, potassium and sodium in up to 326,441 unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression and possible causal genes related to these biomarkers. We identified 78 novel genome-wide significant associations with urinary biomarkers, confirming several previously established associations and providing new insights into the genetic basis of these traits and their connection to chronic diseases. Further, we highlight GATM as causally implicated in the genetic control of urine creatinine, and GIPR, a potential diabetes drug target, as a plausible causal gene involved in regulation of urine creatinine and sodium. The knowledge arising from our work may improve the predictive utility of the respective biomarker and point to new therapeutic strategies to prevent common diseases.

genetics↗

bioRxiv2018

Genetic regulatory mechanisms of smooth muscle cells map to coronary artery disease risk loci

Coronary artery disease (CAD) is the leading cause of death globally. Genome-wide association studies (GWAS) have identified more than 95 independent loci that influence CAD risk, most of which reside in non-coding regions of the genome. To interpret these loci, we generated transcriptome and whole-genome datasets using human coronary artery smooth muscle cells (HCASMC) from 52 unrelated donors, as well as epigenomic datasets using ATAC-seq on a subset of 8 donors. Through systematic comparison with publicly available datasets from GTEx and ENCODE projects, we identified transcriptomic, epigenetic, and genetic regulatory mechanisms specific to HCASMC. We assessed the relevance of HCASMC to CAD risk using transcriptomic and epigenomic level analyses. By jointly modeling eQTL and GWAS datasets, we identified five genes (SIPA1, TCF21, SMAD3, FES, and PDGFRA) that modulate CAD risk through HCASMC, all of which have relevant functional roles in vascular remodeling. Comparison with GTEx data suggests that SIPA1 and PDGFRA influence CAD risk predominantly through HCASMC, while other annotated genes may have multiple cell and tissue targets. Together, these results provide new tissue-specific and mechanistic insights into the regulation of a critical vascular cell type associated with CAD in human populations.

genomics↗

bioRxiv2017

Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases

PurposeBrain metastases from non-small cell lung cancer (NSCLC) engraft and grow either within the brain (solid) or diffusely on its surface (leptomeningeal disease; LMD). Routine clinical diagnostics have low sensitivity and provide no information about the underlying mutations. A recurrent mutation analysis of LMD and a comparison between solid and LMD NSCLC brain metastases have yet to be explored.\n\nExperimental DesignWe performed whole-exome sequencing (WES) on eight cerebrospinal fluid (CSF) specimens from NSCLC LMD patients. We compared our LMD sequencing data with a published data set of 26 NSCLC solid brain metastases to determine the relative mutation frequency. We then performed a retrospective chart review of an additional set of 44 NSCLC LMD patients to further evaluate LMD mutations and clinical prognosis.\n\nResultsSix (75%) LMD cases had mutations in EGFR, while none had KRAS mutations. Retrospective chart review revealed only 4 LMD cases (7.7%) with KRAS mutations, but 33 cases (63.5%) with EGFR mutations. TP53 was mutated in 4/8 LMD (50%) cases and 13/26 of solid metastasis (50%). The median interval for developing LMD from NSCLC was shorter in EGFR-mutant (16.3 mo) than wild-type (23.9 mo) patients (p = 0.017).\n\nConclusionsEGFR and TP53 mutations were frequent in LMD exomes (combined frequency 87.5%), suggesting that PCR-based mutation detection assays towards these two genes could be a useful complement to current diagnostics. Correlations of EGFR in LMD and KRAS in solid metastases suggest molecular distinctions or systemic treatment pressure underpinning differences in growth patterns within the brain.\n\nTranslational RelevanceLeptomeningeal disease is a diffuse, malignant, and incurable metastatic brain tumor that accounts for 5-10% of brain metastases. Patients with LMD do not undergo biopsy and their overall prognosis is poor (median survival 3 to 27 months), making it difficult to collect sufficient samples for recurrent mutation analysis. Standard diagnostic procedures (MRI and cytology) for LMD provide no genetic information. To understand the mutation landscape of LMD, we performed whole-exome sequencing on eight lung-derived LMD cases. We showed that mutations in EGFR occurred more frequently in LMD than solid brain metastases, but KRAS mutations were not present in LMD. Further, mutations in recurrent genes such as EGFR and TP53 could be reliably detected in CSF via droplet digital PCR. Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic toolkit, and differences in mutations between LMD and solid brain metastases suggest distinct molecular mechanisms for growth.

genomics↗

bioRxiv2017

Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke

PCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.

genetics↗