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schizophrenia and inherited disease

John F Fullard, Alexander W Charney, Georgios Voloudakis, Andrew V Uzilov, Vahram Haroutunian, Panos Roussos
The genetic architecture of schizophrenia (SCZ) includes numerous risk loci across a range of frequencies and sizes, including common and rare single-nucleotide variants and insertions/deletions (indels), as well as rare copy number variants (CNVs). Despite the clear heritability of the disease, monozygotic twins are discordant for SCZ at a significant rate. Somatic variants-genetic changes that arise after fertilization rather than through germline inheritance-are widespread in the human brain and known to contribute to risk for both rare and common neuropsychiatric conditions...
January 17, 2019: Translational Psychiatry
Suhas Ganesh, Husayn Ahmed P, Ravi Kumar Nadella, Ravi Prabhakar More, Manasa Sheshadri, Biju Viswanath, Mahendra Rao, Sanjeev Jain, Odity Mukherjee
AIM: Severe Mental Illnesses, such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing may add to the understanding of genetic architecture of SMIs. METHODS: We analyzed 32 ill subjects from 8 multiplex families; and 33 healthy individuals by whole exome sequencing...
October 27, 2018: Psychiatry and Clinical Neurosciences
Mari E K Niemi, Hilary C Martin, Daniel L Rice, Giuseppe Gallone, Scott Gordon, Martin Kelemen, Kerrie McAloney, Jeremy McRae, Elizabeth J Radford, Sui Yu, Jozef Gecz, Nicholas G Martin, Caroline F Wright, David R Fitzpatrick, Helen V Firth, Matthew E Hurles, Jeffrey C Barrett
There are thousands of rare human disorders that are caused by single deleterious, protein-coding genetic variants1 . However, patients with the same genetic defect can have different clinical presentations2-4 , and some individuals who carry known disease-causing variants can appear unaffected5 . Here, to understand what explains these differences, we study a cohort of 6,987 children assessed by clinical geneticists to have severe neurodevelopmental disorders such as global developmental delay and autism, often in combination with abnormalities of other organ systems...
October 2018: Nature
Arveen Kamath, Stefanie C Linden, Ffion M Evans, Jeremy Hall, Sian F Jose, Sally A Spillane, Alan D R Hardie, Sian M Morgan, Daniela T Pilz
Copy number variants at chromosome 17q12 have been associated with a spectrum of phenotypes. Deletions of 17q12 are well described and associated with maturity onset diabetes of the young type 5 (MODY5) and cystic renal disease (HNF1β) as well as cognitive impairment and seizures. Duplication of 17q12 is emerging as a new genetic syndrome, associated with learning disability, seizures, and behavioral problems. The duplication is often inherited from an apparently unaffected parent. Here, we describe a three-generation family with multiple individuals carrying a17q12 microduplication with varying clinical features, consistent with variable penetrance...
July 2018: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Masaki Nishioka, Miki Bundo, Kazuya Iwamoto, Tadafumi Kato
Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene-environment interactions. While recent advances in genomic technologies have enabled the identification of several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions...
August 7, 2018: Molecular Psychiatry
Dimitrios Avramopoulos
The last decade brought tremendous progress in the field of schizophrenia genetics. As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include large copy number variants, rare coding inherited and de novο variants, and over 100 loci harboring common risk variants. While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory...
June 2018: Molecular Neuropsychiatry
Dennis R Grayson, Alessandro Guidotti
Schizophrenia (SZ) is a debilitating disease that impacts 1% of the population worldwide. Association studies have shown that inherited genetic mutations account for a portion of disease risk. However, environmental factors play an important role in the pathophysiology of the disease by altering cellular epigenetic marks at the level of chromatin. Postmortem brain studies of SZ subjects suggest that the dynamic equilibrium between DNA methylation and demethylation network components is disrupted at the level of individual SZ target genes...
2018: Progress in Molecular Biology and Translational Science
Rasmus Nejst Jensen, Tom Bolwig, Sven Asger Sørensen
Huntington's disease is an inherited neuropsychiatric disorder characterized by a triad of symptoms: motor, cognitive and psychiatric. Psychiatric symptoms occur prior to the motor symptoms in approximately 50% of the cases, and knowledge of the psychiatric symptoms is essential in making an early diagnosis. In this article, we argue that further knowledge of the genetic background of Huntington's disease may contribute to a better understanding of the polygenetic psychiatric diseases such as schizophrenia and bipolar affective disorder...
March 26, 2018: Ugeskrift for Laeger
Maria Pia Giannoccaro, Anna Bartoletti-Stella, Silvia Piras, Alfonsina Casalena, Federico Oppi, Giovanni Ambrosetto, Pasquale Montagna, Rocco Liguori, Piero Parchi, Sabina Capellari
BACKGROUND: In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. OBJECTIVE: To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). METHODS: We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals...
2018: Journal of Alzheimer's Disease: JAD
Peng Liu, Zhongwei Liu, Jiabei Wang, Xiancang Ma, Yonghui Dang
Although many studies have investigated the functions of histidine triad nucleotide-binding protein 1 (HINT1), its roles in neurobiological processes remain to be fully elucidated. As a member of the histidine triad (HIT) enzyme superfamily, HINT1 is distributed in almost every organ and has both enzymatic and nonenzymatic activity. Accumulating clinical and preclinical evidence suggests that HINT1 may play an important role as a neuroplastic mediator in neuropsychiatric diseases, such as schizophrenia, inherited peripheral neuropathies, mood disorders, and drug addiction...
2017: Neural Plasticity
Maneesh K Misra, Vincent Damotte, Jill A Hollenbach
Genes encoding antigen-presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin-like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis...
April 2018: Immunology
Yong-Hui Dang, Zhong-Wei Liu, Peng Liu, Jia-Bei Wang
The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities...
October 30, 2017: Zhongguo Yi Xue Ke Xue Yuan Xue Bao. Acta Academiae Medicinae Sinicae
Andrzej Witusik
Qualitative analysis of the family system including a person suffering from schizophrenia is an underestimated research paradigm in modern psychiatry, clinical psychology and psychotherapy. This method is important both from the cognitive point of view and for evaluation of the effectiveness of therapy. AIM: The aim of the study was a qualitative analysis of the therapeutic process in a family whose member is suffering from schizophrenic psychosis. MATERIALS AND METHODS: The study of the process using qualitative research methodology in the paradigm of systemic thinking pointing to the mutual interactions in the family system inducing relapses in the identified patient, with identification of triangulation processes, transgenerational myths inheritance and coalitions formed by the family members...
July 21, 2017: Polski Merkuriusz Lekarski: Organ Polskiego Towarzystwa Lekarskiego
A Yu Morozova, E A Zubkov, Ya A Zorkina, A M Reznik, G P Kostyuk, V P Chekhonin
Schizophrenia is a disease with a complex non-Mendelian inheritance mechanism in most cases involving the combined action of a large number of genes. Identifying of genomic variations associated with schizophrenia endophenotypes has a great potential. This review describes genetic markers of the disease, current methods of their analysis, including genome-wide association study (GWAS). Certain genes with mutations that increase the risk of schizophrenia are described. Functional polymorphisms with phenotypic expression, which are significantly associated with clinical manifestation of schizophrenia, can serve as useful genetic markers...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
Daniel J Weiner, Emilie M Wigdor, Stephan Ripke, Raymond K Walters, Jack A Kosmicki, Jakob Grove, Kaitlin E Samocha, Jacqueline I Goldstein, Aysu Okbay, Jonas Bybjerg-Grauholm, Thomas Werge, David M Hougaard, Jacob Taylor, David Skuse, Bernie Devlin, Richard Anney, Stephan J Sanders, Somer Bishop, Preben Bo Mortensen, Anders D Børglum, George Davey Smith, Mark J Daly, Elise B Robinson
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD...
July 2017: Nature Genetics
A Devor, O A Andreassen, Y Wang, T Mäki-Marttunen, O B Smeland, C-C Fan, A J Schork, D Holland, W K Thompson, A Witoelar, C-H Chen, R S Desikan, L K McEvoy, S Djurovic, P Greengard, P Svenningsson, G T Einevoll, A M Dale
The most recent genome-wide association studies (GWAS) of schizophrenia (SCZ) identified hundreds of risk variants potentially implicated in the disease. Further, novel statistical methodology designed for polygenic architecture revealed more potential risk variants. This can provide a link between individual genetic factors and the mechanistic underpinnings of SCZ. Intriguingly, a large number of genes coding for ionotropic and metabotropic receptors for various neurotransmitters-glutamate, γ-aminobutyric acid (GABA), dopamine, serotonin, acetylcholine and opioids-and numerous ion channels were associated with SCZ...
June 2017: Molecular Psychiatry
Tianqi Wang, Xiaolong Zhang, Ang Li, Meifang Zhu, Shu Liu, Wen Qin, Jin Li, Chunshui Yu, Tianzi Jiang, Bing Liu
Major psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), autism (AUT), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SZ), are highly heritable and polygenic. Evidence suggests that these five disorders have both shared and distinct genetic risks and neural connectivity abnormalities. To measure aggregate genetic risks, the polygenic risk score (PGRS) was computed. Two independent general populations (N = 360 and N = 323) were separately examined to investigate whether the cross-disorder PGRS and PGRS for a specific disorder were associated with individual variability in functional connectivity...
2017: NeuroImage: Clinical
Tobias Hornig, Björn Grüning, Kousik Kundu, Torsten Houwaart, Rolf Backofen, Knut Biber, Claus Normann
Glutamate is the most important excitatory neurotransmitter in the brain. The N-methyl-D-aspartate (NMDA) receptor is a glutamate-gated ionotropic cation channel that is composed of several subunits and modulated by a glycine binding site. Many forms of synaptic plasticity depend on the influx of calcium ions through NMDA receptors, and NMDA receptor dysfunction has been linked to a number of neuropsychiatric disorders, including schizophrenia. Whole-exome sequencing was performed in a family with a strong history of psychotic disorders over three generations...
January 30, 2017: Genetics Research
Ina Giegling, Ladislav Hosak, Rainald Mössner, Alessandro Serretti, Frank Bellivier, Stephan Claes, David A Collier, Alejo Corrales, Lynn E DeLisi, Carla Gallo, Michael Gill, James L Kennedy, Marion Leboyer, Wolfgang Maier, Miguel Marquez, Isabelle Massat, Ole Mors, Pierandrea Muglia, Markus M Nöthen, Jorge Ospina-Duque, Michael J Owen, Peter Propping, YongYong Shi, David St Clair, Florence Thibaut, Sven Cichon, Julien Mendlewicz, Michael C O'Donovan, Dan Rujescu
OBJECTIVES: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes. METHODS: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing...
October 2017: World Journal of Biological Psychiatry
Karin J H Verweij, Abdel Abdellaoui, Michel G Nivard, Alberto Sainz Cort, Lannie Ligthart, Harmen H M Draisma, Camelia C Minică, Nathan A Gillespie, Gonneke Willemsen, Jouke-Jan Hottenga, Dorret I Boomsma, Jacqueline M Vink
BACKGROUND AND AIM: Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use. METHODS: Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date...
February 1, 2017: Drug and Alcohol Dependence
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