Nirmal Vadgama

All Publications

• Mapping the human genetic architecture of COVID-19. Nature COVID-19 Host Genetics Initiative 2021

  Abstract

  The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity1,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprised of up to 49,562 COVID-19 patients from 46 studies across 19 countries. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3-7. They also represent potentially actionable mechanisms in response to infection. Mendelian Randomization analyses support a causal role for smoking and body mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was made possible by the community of human genetic researchers coming together to prioritize sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

  View details for DOI 10.1038/s41586-021-03767-x

  View details for PubMedID 34237774

• The Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy. Circulation Feyen, D. A., Perea-Gil, I., Maas, R. G., Harakalova, M., Gavidia, A. A., Arthur Ataam, J., Wu, T., Vink, A., Pei, J., Vadgama, N., Suurmeijer, A. J., Te Rijdt, W. P., Vu, M., Amatya, P. L., Prado, M., Zhang, Y., Dunkenberger, L., Sluijter, J. P., Sallam, K., Asselbergs, F. W., Mercola, M., Karakikes, I. 2021

  Abstract

  Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy (DCM) with a high prevalence of ventricular arrhythmias. How the R14 deletion causes DCM is poorly understood and there are no disease-specific therapies. Methods: We used single-cell RNA sequencing to uncover PLN R14del disease-mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We utilized both 2D and 3D functional contractility assays to evaluate the impact of modulating disease relevant pathways in PLN R14del hiPSC-CMs. Results: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro. Single-cell RNA sequencing revealed the induction of the unfolded protein response pathway (UPR) in PLN R14del compared to isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the three main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP protein Inducer X (BiX). PLN R14del hiPSC-CMs treated with BiX showed a dose-dependent amelioration of the contractility deficit of in both 2D cultures and 3D engineered heart tissues without affecting calcium homeostasis. Conclusions: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.

  View details for DOI 10.1161/CIRCULATIONAHA.120.049844

  View details for PubMedID 33928785

• Small-molecule probe reveals a kinase cascade that links stress signaling to TCF/LEF and Wnt responsiveness. Cell chemical biology Cheng, J. n., Tsuda, M. n., Okolotowicz, K. n., Dwyer, M. n., Bushway, P. J., Colas, A. R., Lancman, J. J., Schade, D. n., Perea-Gil, I. n., Bruyneel, A. A., Lee, J. n., Vadgama, N. n., Quach, J. n., McKeithan, W. L., Biechele, T. L., Wu, J. C., Moon, R. T., Si Dong, P. D., Karakikes, I. n., Cashman, J. R., Mercola, M. n. 2021

  Abstract

  Wnt signaling plays a central role in tissue maintenance and cancer. Wnt activates downstream genes through β-catenin, which interacts with TCF/LEF transcription factors. A major question is how this signaling is coordinated relative to tissue organization and renewal. We used a recently described class of small molecules that binds tubulin to reveal a molecular cascade linking stress signaling through ATM, HIPK2, and p53 to the regulation of TCF/LEF transcriptional activity. These data suggest a mechanism by which mitotic and genotoxic stress can indirectly modulate Wnt responsiveness to exert coherent control over cell shape and renewal. These findings have implications for understanding tissue morphogenesis and small-molecule anticancer therapeutics.

  View details for DOI 10.1016/j.chembiol.2021.01.001

  View details for PubMedID 33503403

• Activation of CaMKII Signaling Pathway Contributes to the Pathogenesis of Genetic Hypertrophic Cardiomyopathy Gil, I., Bellbachir, N., Gavidia, A. A., Arthur, J., Zhang, Y., Vadgama, N., Oikonomopoulos, A., Roura, S., Wu, J. C., Bayes-Genis, A., Karakikes, I. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for DOI 10.1161/res.127.suppl_1.274

  View details for Web of Science ID 000606541500059

• The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic EUROPEAN JOURNAL OF HUMAN GENETICS Covid 19 Host Genetics Initiative 2020; 28 (6): 715-718

  View details for DOI 10.1038/s41431-020-0636-6

  View details for Web of Science ID 000532636000002

  View details for PubMedID 32404885

  View details for PubMedCentralID PMC7220587

• De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes EUROPEAN JOURNAL OF HUMAN GENETICS Vadgama, N., Pittman, A., Simpson, M., Nirmalananthan, N., Murray, R., Yoshikawa, T., De Rijk, P., Rees, E., Kirov, G., Hughes, D., Fitzgerald, T., Kristiansen, M., Pearce, K., Cerveira, E., Zhu, Q., Zhang, C., Lee, C., Hardy, J., Nasir, J. 2019; 27 (7): 1121-1133

  Abstract

  Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n = 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant in PLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I gene MT-ND5 associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlapping ARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent-offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant in RASD2 shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlapping CD38, a gene previously implicated in ASD. In twins discordant for Tourette's syndrome, a paternally inherited stop loss variant was detected in AADAC, a known candidate gene for the disorder.

  View details for DOI 10.1038/s41431-019-0376-7

  View details for Web of Science ID 000471871000014

  View details for PubMedID 30886340

  View details for PubMedCentralID PMC6777616

• Distinct proteomic profiles in monozygotic twins discordant for ischaemic stroke MOLECULAR AND CELLULAR BIOCHEMISTRY Vadgama, N., Lamont, D., Hardy, J., Nasir, J., Lovering, R. C. 2019; 456 (1-2): 157-165

  Abstract

  Stroke is a common disorder with significant morbidity and mortality, and complex aetiology involving both environmental and genetic risk factors. Although some of the major risk factors for stoke, such as smoking and hypertension, are well-documented, the underlying genetic and detailed molecular mechanisms remain elusive. Exploring the relevant biochemical pathways may contribute to the clinical diagnosis of stroke and shed light on its aetiology. A comparative proteomic analysis of blood serum of a pair of monozygotic (MZ) twins discordant for ischaemic stroke (IS) was performed using a label-free quantitative proteomics approach. To overcome the limit of reproducibility in the serum preparation, two separate runs were performed, each consisting of three technical replicates per sample. Biological processes associated with proteins differentially expressed between the twins were explored with gene ontology (GO) classification using the functional analysis tool g:Profiler. ANOVA test performed in Progenesis LC-MS identified 179 (run 1) and 209 (run 2) proteins as differentially expressed between the affected and unaffected twin (p < 0.05). Furthermore, the level of serum fibulin 1, an extracellular matrix protein associated with arterial stiffness, was on average 13.37-fold higher in the affected twin. Each dataset was then analysed independently, and the proteins were classified according to GO terms. The categories overrepresented in the affected twin predominantly corresponded to stroke-relevant processes, including wound healing, blood coagulation and haemostasis, with a high proportion of the proteins overexpressed in the affected twin associated with these terms. By contrast, in the unaffected twin diagnosed with atopic dermatitis, there were increased levels of keratin proteins and GO terms associated with skin development. The identification of cellular pathways enriched in IS as well as the upregulation of fibulin 1 sheds new light on the underlying disease-causing mechanisms at the molecular level. Our findings of distinct proteomic signatures associated with IS and atopic dermatitis suggest proteomic profiling could be used as a general approach for improved diagnostic, prognostic and therapeutic strategies.

  View details for DOI 10.1007/s11010-019-03501-2

  View details for Web of Science ID 000466497700015

  View details for PubMedID 30694515

• A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities BRAIN Jelani, M., Dooley, H. C., Gubas, A., Mohamoud, H., Khan, M., Ali, Z., Kang, C., Rahim, F., Jan, A., Vadgama, N., Khan, M., Al-Aama, J., Khan, A., Tooze, S. A., Nasir, J. 2019; 142: 1242-1254

  Abstract

  We describe a large consanguineous pedigree from a remote area of Northern Pakistan, with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. We initially carried out a genetic study using the HumanCytoSNP-12 v2.1 Illumina gene chip on nine family members and identified a single region of homozygosity shared amongst four affected individuals on chromosome 7p22 (positions 3059377-5478971). We performed whole-exome sequencing on two affected individuals from two separate branches of the extended pedigree and identified a novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene at position 5265458 (c.G745A;pV249M). WIPI2 plays a critical role in autophagy, an evolutionary conserved cellular pathway implicated in a growing number of medical conditions. The mutation is situated in a highly conserved and critically important region of WIPI2, responsible for binding PI(3)P and PI(3,5)P2, an essential requirement for autophagy to proceed. The mutation is absent in all public databases, is predicted to be damaging and segregates with the disease phenotype. We performed functional studies in vitro to determine the potential effects of the mutation on downstream pathways leading to autophagosome assembly. Binding of the V231M mutant of WIPI2b to ATG16L1 (as well as ATG5-12) is significantly reduced in GFP pull-down experiments, and fibroblasts derived from the patients show reduced WIPI2 puncta, reduced LC3 lipidation and reduced autophagic flux.

  View details for DOI 10.1093/brain/awz075

  View details for Web of Science ID 000481420000019

  View details for PubMedID 30968111

  View details for PubMedCentralID PMC6487338

• A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features SCIENTIFIC REPORTS Mohamoud, H., Ahmed, S., Jelani, M., Alrayes, N., Childs, K., Vadgama, N., Almramhi, M., Al-Aama, J., Goodbourn, S., Nasir, J. 2018; 8: 2053

  Abstract

  Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities.

  View details for DOI 10.1038/s41598-018-20658-w

  View details for Web of Science ID 000423787500028

  View details for PubMedID 29391579

  View details for PubMedCentralID PMC5794855

• Truncating mutation in intracellular phospholipase A₁ gene (DDHD2) in hereditary spastic paraplegia with intellectual disability (SPG54). BMC research notes Alrayes, N., Mohamoud, H. S., Jelani, M., Ahmad, S., Vadgama, N., Bakur, K., Simpson, M., Al-Aama, J. Y., Nasir, J. 2015; 8: 271

  Abstract

  BACKGROUND: Hereditary spastic paraplegias (HSP), a group of genetically heterogeneous neurological disorders with more than 56 documented loci (SPG1-56), are described either as uncomplicated (or pure), or complicated where in addition to spasticity and weakness of lower extremeties, additional neurological symptoms are present, including dementia, loss of vision, epilepsy, mental retardation and ichthyosis. We identified a large consanguineous family of Indian descent with four affected members with childhood onset HSP (SPG54), presenting with upper and lower limb spasticity, mental retardation and agenesis of the corpus callosum.RESULTS: A common region of homozygosity on chromosome 8 spanning seven megabases (Mb) was identified in the affected individuals using the Illumina human cytoSNP-12 DNA Analysis BeadChip Kit. Exome sequencing identified a homozygous stop gain mutation (pR287X) in the phospholipase A1 gene DDHD2, in the affected individuals, resulting in a premature stop codon and a severely truncated protein lacking the SAM and DDHD domains crucial for phosphoinositide binding and phospholipase activity.CONCLUSION: This mutation adds to the knowledge of HSP, suggests a possible founder effect for the pR287X mutation, and adds to the list of genes involved in lipid metabolism with a role in HSP and other neurodegenerative disorders.

  View details for DOI 10.1186/s13104-015-1227-4

  View details for PubMedID 26113134

• Elevated gamma-glutamyltransferase and erythrocyte sedimentation rate in ischemic stroke in discordant monozygotic twin study INTERNATIONAL JOURNAL OF STROKE Vadgama, N., Gaze, D., Ranson, J., Hardy, J., Nasir, J. 2015; 10 (4): E32-E33

  View details for DOI 10.1111/ijs.12440

  View details for Web of Science ID 000354494000001

  View details for PubMedID 25973705