Bharti Morar

Harry Perkins Institute of Medical Research

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Luba Kalaydjieva

University of Western Australia

Assen Jablensky

University of Western Australia

Dimitar N. Azmanov

Pathwest Laboratory Medicine

Dora Angelicheva

Harry Perkins Institute of Medical Research

Ivailo Tournev

New Bulgarian University

David Chandler

University of Westminster

Velina Guergueltcheva

Medical University of Sofia

Radka Kaneva

Medical University of Sofia

Himla Soodyall

University of the Witwatersrand

Milan Dragović

University of Western Australia

Cooperative Institutions

University of Western Australia

Harry Perkins Institute of Medical Research

Medical University of Sofia

University College London

Inserm

Centre National de la Recherche Scientifique

Université Paris Cité

Queen Elizabeth II Medical Centre

Ludwig-Maximilians-Universität München

Assistance Publique – Hôpitaux de Paris

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Psychosis Susceptibility Gene ZNF804A and Cognitive Performance in Schizophrenia

Archives of General Psychiatry (2010)

James Walters Aiden Corvin Michael J. Owen Hywel Williams Milan Dragović

Context

The Zinc Finger Protein 804A gene (ZNF804A) has been implicated in schizophrenia susceptibility by several genome-wide association studies.ZNF804Ais brain expressed but of unknown function.

Objective

To investigate whether the identified risk allele at the disease-associated single nucleotide polymorphism rs1344706 is associated with variation in neuropsychological performance in patients and controls.

Design

Comparison of cases and controls grouped according toZNF804Agenotype (AAvsACvsCC) on selected measures of cognition in 2 independent samples.

Setting

Unrelated patients from general adult psychiatric inpatient and outpatient services and unrelated healthy participants from the general population were ascertained.

Participants

Patients withDSM-IV–diagnosed schizophrenia and healthy participants from independent samples of Irish (297 cases and 165 controls) and German (251 cases and 1472 controls) nationality.

Main Outcome Measures

In this 2-stage study, we tested for an association betweenZNF804Ars1344706 and cognitive functions known to be impaired in schizophrenia (IQ, episodic memory, working memory, and attention) in an Irish discovery sample. We then tested significant results in a German replication sample.

Results

In the Irish samples, theZNF804Agenotype was associated with differences in episodic and working memory in patients but not in controls. These findings replicated in the same direction in the German samples. Furthermore, in both samples, when patients with a lower IQ were excluded, the association betweenZNF804Aand schizophrenia strengthened.

Conclusions

In a disorder characterized by heterogeneity, a risk variant atZNF804Aseems to delineate a patient subgroup characterized by relatively spared cognitive ability. Further work is required to establish whether this represents a discrete molecular pathogenesis that differs from that of other patient groups and whether this also has consequences for nosologic classification, illness course, or treatment.

10.1001/archgenpsychiatry.2010.81

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Citations (147)

Integrin Alpha 8 Recessive Mutations Are Responsible for Bilateral Renal Agenesis in Humans

The American Journal of Human Genetics (2014)

Camille Humbert Flora Silbermann Bharti Morar Mélanie Parisot Mohammed Zarhrate

Renal agenesis

Sanger sequencing

Agenesis

Renal dysplasia

10.1016/j.ajhg.2014.04.013

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Citations (2)

The AQP1 del601G mutation in different European Romani (Gypsy) populations.

PubMed (2016)

Brigitte K. Flesch Bharti Morar David Comas Eduardo Muñiz‐Díaz Núria Nogués

10.2450/2016.0274-15

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Citations (1)

Roma (Gypsies): Genetic Studies

Encyclopedia of Life Sciences (2006)

Luba Kalaydjieva Bharti Morar

Abstract The Roma, also known as Gypsies, are a transnational founder population, resembling a mosaic of socially and genetically divergent groups. Common origins from a small group of related founders result in sharing of maternal and paternal lineages and of ancient disease‐causing mutations across endogamous Romani groups in different countries. Genetic differentiation between groups, with an impact on genetic epidemiology, is the product of bottleneck events, random genetic drift and differential admixture, and correlates with the migrational history of the Roma in Europe.

Endogamy

Founder effect

Genetic drift

Population bottleneck

Genetic epidemiology

10.1002/9780470015902.a0006239

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Citations (0)

Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

Faculty of Health; Institute of Health and Biomedical Innovation (2014)

Иван Иванов Dimitar N. Azmanov M. Ivanova Teodora Chamova Ilyana H. Pacheva

Lactic acidosis

Psychomotor retardation

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Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease

Human Mutation (2003)

Michael Hunter Rafaëlle Bernard Elizabeth Freitas Amandine Boyer Bharti Morar

In a previous study, we have shown that N-myc downstream-regulated gene 1 (NDRG1), classified in databases as a tumor suppressor and heavy metal-response protein, is mutated in hereditary motor and sensory neuropathy Lom (HMSNL), a severe autosomal recessive form of Charcot-Marie-Tooth (CMT) disease. The private founder mutation R148X, causing HMSNL in patients of Romani ethnicity, has so far remained the only molecular defect linking NDRG1 to a specific disease phenotype. Here we report the first study aiming to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease have been excluded. Sequence analysis of NDRG1 in 104 CMT patients of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9. The phenotype of the IVS8-1G>A homozygote was very closely related to that of HMSNL patients. In addition, we have detected homozygosity for the known R148X mutation in two affected individuals. Mutations in NDRG1 thus accounted for 2.88% of our overall group of patients, and for 4.68% of cases with demyelinating neuropathies. No other variants were identified in the coding sequence, whereas 12 single nucleotide polymorphisms were observed in the introns. Hum Mutat 22:129-135, 2003.

Coding region

Pathogenesis

Founder effect

10.1002/humu.10240

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Citations (51)

A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine

Neurology (2018)

Macarena Cabrera‐Serrano Fabiola Mavillard Valérie Biancalana Eloy Rivas Bharti Morar

To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified.Patients diagnosed with centronuclear myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed.Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma.We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

Founder effect

Compound heterozygosity

Congenital myopathy

10.1212/wnl.0000000000005862

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Citations (20)

The Human Genome as Archive: Some Illustrations from the South

Springer eBooks (2002)

Himla Soodyall Bharti Morar Trefor Jenkins

Feature (linguistics)

10.1007/978-94-010-0570-8_11

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Citations (13)

Deleterious GRM1 Mutations in Schizophrenia

PLoS ONE (2012)

Mohammed Akli Ayoub Dora Angelicheva David Vile David Chandler Bharti Morar

We analysed a phenotypically well-characterised sample of 450 schziophrenia patients and 605 controls for rare non-synonymous single nucleotide polymorphisms (nsSNPs) in the GRM1 gene, their functional effects and family segregation. GRM1 encodes the metabotropic glutamate receptor 1 (mGluR1), whose documented role as a modulator of neuronal signalling and synaptic plasticity makes it a plausible schizophrenia candidate. In a recent study, this gene was shown to harbour a cluster of deleterious nsSNPs within a functionally important domain of the receptor, in patients with schizophrenia and bipolar disorder. Our Sanger sequencing of the GRM1 coding regions detected equal numbers of nsSNPs in cases and controls, however the two groups differed in terms of the potential effects of the variants on receptor function: 6/6 case-specific and only 1/6 control-specific nsSNPs were predicted to be deleterious. Our in-vitro experimental follow-up of the case-specific mutants showed that 4/6 led to significantly reduced inositol phosphate production, indicating impaired function of the major mGluR1signalling pathway; 1/6 had reduced cell membrane expression; inconclusive results were obtained in 1/6. Family segregation analysis indicated that these deleterious nsSNPs were inherited. Interestingly, four of the families were affected by multiple neuropsychiatric conditions, not limited to schizophrenia, and the mutations were detected in relatives with schizophrenia, depression and anxiety, drug and alcohol dependence, and epilepsy. Our findings suggest a possible mGluR1 contribution to diverse psychiatric conditions, supporting the modulatory role of the receptor in such conditions as proposed previously on the basis of in vitro experiments and animal studies.

10.1371/journal.pone.0032849

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Citations (65)

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

European Journal of Human Genetics (2010)

Dimitar N. Azmanov С. Димитрова Laura Flórez Sylvia Cherninkova Dragomir Draganov

Ectopia lentis

Founder effect

Disease gene identification

Allelic heterogeneity

10.1038/ejhg.2010.181

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Citations (65)