[S4.4]: The genetic architecture of autism: What can common SNP association tell us about rare copy number variants?

AbstractRare and large copy number variants (CNVs) around known genomic ‘hotspots’ are strongly implicated in epilepsy etiology. But it remains unclear whether the observed associations are specific to an epilepsy phenotype, and if additional risk signal can be found outside hotspots. Here, we present the largest CNV burden and first CNV breakpoint level association analysis in epilepsy to date with 11,246 European epilepsy cases and 7,318 ancestry-matched controls. We studied five epilepsy phenotypes: genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, epileptic encephalopathy, and unclassified epilepsy. We discovered novel epilepsy-associated CNV loci and further characterized the CNV burden enrichment among phenotype-specific epilepsies. Finally, we provide evidence for deletion burden outside of known hotspot regions and show that CNVs play a significant role in the genetic architecture of lesional focal epilepsies.

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Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome

10.1101/062471 ◽

2016 ◽

Cited By ~ 3

Author(s):

Alden Y. Huang ◽

Dongmei Yu ◽

Lea K. Davis ◽

Jae-Hoon Sul ◽

Fotis Tsetsos ◽

...

Keyword(s):

Tourette Syndrome ◽

Copy Number ◽

Genetic Architecture ◽

Structural Variation ◽

Copy Number Variants ◽

European Ancestry ◽

Genome Wide ◽

Snp Microarrays ◽

Increase Risk ◽

Increase In Risk

Tourette syndrome (TS) is highly heritable, although identification of its underlying genetic cause(s) has remained elusive. We examined a European ancestry sample composed of 2,435 TS cases and 4,100 controls for copy-number variants (CNVs) using SNP microarrays and identified two genome-wide significant loci that confer a substantial increase in risk for TS (NRXN1, OR=20.3, 95%CI [2.6-156.2], p=6.0 × 10−6; CNTN6, OR=10.1, 95% CI [2.3-45.4], p=3.7 × 10−5). Approximately 1% of TS cases carried one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.

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Update on the genetic architecture of schizophrenia

Medizinische Genetik ◽

10.1515/medgen-2020-2009 ◽

2020 ◽

Vol 32 (1) ◽

pp. 19-24

Author(s):

Franziska Degenhardt

Keyword(s):

Neurodevelopmental Disorders ◽

Genetic Risk ◽

Copy Number ◽

Genetic Architecture ◽

Genetic Variant ◽

Chromosomal Region ◽

Copy Number Variants ◽

Individual Risk ◽

Diagnostic Investigation ◽

Rare Alleles

Abstract A long-established hypothesis is that schizophrenia has a strong genetic component. In the early 1990s, the first genetic variant that substantially increases risk for psychosis was identified. Since this initial reporting of deletions in the chromosomal region 22q11.2, nearly two decades passed until substantial insights into schizophrenia’s genetic architecture were gained. Schizophrenia is a polygenic disorder and genetic risk is conferred by both common and rare alleles distributed across the genome. A small number of rare, deleterious copy number variants (CNVs) are associated with moderate to substantial increases in individual risk to schizophrenia. These deletions and duplications are also associated with a range of neurodevelopmental disorders. The diagnostic investigation of CNVs in patients with schizophrenia is likely to represent one of the first examples of genetic testing in clinical psychiatry. The prerequisites for this are currently being defined.

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Understanding Schizophrenia: Genetic Causes and Treatment

Current Neuropsychiatry and Clinical Neuroscience Reports ◽

10.33702/cncnr.2019.1.1.2 ◽

2019 ◽

Vol 1 (1) ◽

pp. 6-12

Author(s):

Fatima Javeria ◽

Shazma Altaf ◽

Alishah Zair ◽

Rana Khalid Iqbal

Keyword(s):

Copy Number ◽

Drug Targets ◽

Disease Risk ◽

Mental Disease ◽

Copy Number Variants ◽

Aminobutyric Acid ◽

Epigenetic Mechanisms ◽

Gamma Aminobutyric Acid ◽

Wide Range ◽

Severe Mental Disease

Schizophrenia is a severe mental disease. The word schizophrenia literally means split mind. There are three major categories of symptoms which include positive, negative and cognitive symptoms. The disease is characterized by symptoms of hallucination, delusions, disorganized thinking and speech. Schizophrenia is related to many other mental and psychological problems like suicide, depression, hallucinations. Including these, it is also a problem for the patient’s family and the caregiver. There is no clear reason for the disease, but with the advances in molecular genetics; certain epigenetic mechanisms are involved in the pathophysiology of the disease. Epigenetic mechanisms that are mainly involved are the DNA methylation, copy number variants. With the advent of GWAS, a wide range of SNPs is found linked with the etiology of schizophrenia. These SNPs serve as ‘hubs’; because these all are integrating with each other in causing of schizophrenia risk. Until recently, there is no treatment available to cure the disease; but anti-psychotics can reduce the disease risk by minimizing its symptoms. Dopamine, serotonin, gamma-aminobutyric acid, are the neurotransmitters which serve as drug targets in the treatment of schizophrenia. Due to the involvement of genetic and epigenetic mechanisms, drugs available are already targeting certain genes involved in the etiology of the disease.

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