scholarly journals Integration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11.2 CNV genes

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Mikhail Vysotskiy ◽  
Xue Zhong ◽  
Tyne W. Miller-Fleming ◽  
Dan Zhou ◽  
Nancy J. Cox ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Clinical Data ◽  
Copy Number ◽  
Association Studies ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Full Spectrum ◽  
Individual Gene ◽  
Association Testing ◽  
Electronic Health

Abstract Background Deletions and duplications of the multigenic 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including schizophrenia, intellectual disability, obesity, bipolar disorder, and autism spectrum disorder (ASD). The contribution of individual CNV genes to each of these identified phenotypes is unknown, as well as the contribution of these CNV genes to other potentially subtler health implications for carriers. Hypothesizing that DNA copy number exerts most effects via impacts on RNA expression, we attempted a novel in silico fine-mapping approach in non-CNV carriers using both GWAS and biobank data. Methods We first asked whether gene expression level in any individual gene in the CNV region alters risk for a known CNV-associated behavioral phenotype(s). Using transcriptomic imputation, we performed association testing for CNV genes within large genotyped cohorts for schizophrenia, IQ, BMI, bipolar disorder, and ASD. Second, we used a biobank containing electronic health data to compare the medical phenome of CNV carriers to controls within 700,000 individuals in order to investigate the full spectrum of health effects of the CNVs. Third, we used genotypes for over 48,000 individuals within the biobank to perform phenome-wide association studies between imputed expressions of individual 16p11.2 and 22q11.2 genes and over 1500 health traits. Results Using large genotyped cohorts, we found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2, INO80E), and IQ (SPN), using conditional analysis to identify upregulation of INO80E as the driver of schizophrenia, and downregulation of SPN and INO80E as increasing BMI. We identified both novel and previously observed over-represented traits within the electronic health records of 16p11.2 and 22q11.2 CNV carriers. In the phenome-wide association study, we found seventeen significant gene-trait pairs, including psychosis (NPIPB11, SLX1B) and mood disorders (SCARF2), and overall enrichment of mental traits. Conclusions Our results demonstrate how integration of genetic and clinical data aids in understanding CNV gene function and implicates pleiotropy and multigenicity in CNV biology.

scholarly journals tiIntegration of genetic, transcriptomic, and clinical data provides insight into 16p11.2 and 22q11.2 CNV genes

2020 ◽  
Author(s):  
Mikhail Vysotskiy ◽  
Xue Zhong ◽  
Tyne W. Miller-Fleming ◽  
Dan Zhou ◽  
Nancy J. Cox ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Clinical Data ◽  
Copy Number ◽  
Association Studies ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Individual Gene ◽  
Association Testing ◽  
Significant Gene ◽  
Insight Into

ABSTRACTDeletions and duplications of the multigenic 16p11.2 and 22q11.2 copy number variant (CNV) regions are associated with brain-related disorders including schizophrenia, intellectual disability, obesity, bipolar disorder, and autism spectrum disorder (ASD). The contribution of individual CNV genes to each phenotype is unknown. As DNA copy number impacts RNA expression, we attempted a novel in silico fine-mapping approach in the general population by asking whether gene expression level in any individual gene in the CNV region impacts risk for the same disorder(s). Using transcriptomic imputation, we first performed association testing for CNV genes within large genotyped cohorts for schizophrenia, IQ, BMI, bipolar disorder, and ASD. We found individual genes within 16p11.2 associated with schizophrenia (TMEM219, INO80E, YPEL3), BMI (TMEM219, SPN, TAOK2, INO80E), and IQ (SPN), using conditional analysis to identify INO80E as the driver of schizophrenia, and SPN and INO80E as drivers of BMI in the expected direction. Second, we used a biobank containing electronic health data to compare the medical phenome of CNV carriers to controls within 700,000 individuals, identifying both novel and previously observed traits. Third, we used genotypes for over 48,000 individuals within the biobank to perform phenome-wide association studies between imputed expressions of individual 16p11.2 and 22q11.2 genes and over 1,500 health traits, finding seventeen significant gene-trait pairs, including psychosis (NPIPB11, SLX1B) and mood disorders (SCARF2), and overall enrichment of mental traits. Our results demonstrate how integration of genetic and clinical data aids in understanding CNV gene function, and implicate pleiotropy and multigenicity in CNV biology.

scholarly journals Prediction of response to drug therapy in psychiatric disorders

Open Biology ◽  
2018 ◽  
Vol 8 (5) ◽  
pp. 180031 ◽  
Author(s):  
Shani Stern ◽  
Sara Linker ◽  
Krishna C. Vadodaria ◽  
Maria C. Marchetto ◽  
Fred H. Gage
Keyword(s):  
Autism Spectrum Disorder ◽  
Bipolar Disorder ◽  
Major Depression ◽  
Personalized Medicine ◽  
Psychiatric Disorders ◽  
Association Studies ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide Association Studies ◽  
Patient Reported

Personalized medicine has become increasingly relevant to many medical fields, promising more efficient drug therapies and earlier intervention. The development of personalized medicine is coupled with the identification of biomarkers and classification algorithms that help predict the responses of different patients to different drugs. In the last 10 years, the Food and Drug Administration (FDA) has approved several genetically pre-screened drugs labelled as pharmacogenomics in the fields of oncology, pulmonary medicine, gastroenterology, haematology, neurology, rheumatology and even psychiatry. Clinicians have long cautioned that what may appear to be similar patient-reported symptoms may actually arise from different biological causes. With growing populations being diagnosed with different psychiatric conditions, it is critical for scientists and clinicians to develop precision medication tailored to individual conditions. Genome-wide association studies have highlighted the complicated nature of psychiatric disorders such as schizophrenia, bipolar disorder, major depression and autism spectrum disorder. Following these studies, association studies are needed to look for genomic markers of responsiveness to available drugs of individual patients within the population of a specific disorder. In addition to GWAS, the advent of new technologies such as brain imaging, cell reprogramming, sequencing and gene editing has given us the opportunity to look for more biomarkers that characterize a therapeutic response to a drug and to use all these biomarkers for determining treatment options. In this review, we discuss studies that were performed to find biomarkers of responsiveness to different available drugs for four brain disorders: bipolar disorder, schizophrenia, major depression and autism spectrum disorder. We provide recommendations for using an integrated method that will use available techniques for a better prediction of the most suitable drug.

PSVIII-10 Genome-wide CNV analysis unravels a deletion associated with parasite resistance in Florida native sheep

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 243-244
Author(s):  
Brittany N Diehl ◽  
Andres A Pech-Cervantes ◽  
Thomas H Terrill ◽  
Ibukun M Ogunade ◽  
Owen Rae ◽  
...  
Keyword(s):  
Copy Number ◽  
Association Studies ◽  
Chromosome 21 ◽  
Trend Test ◽  
P Value ◽  
Genome Wide Association Studies ◽  
Parasite Resistance ◽  
Association Testing ◽  
Genome Wide ◽  
Native Sheep

Abstract Florida Native sheep is an indigenous breed from Florida and expresses superior parasite resistance. Previous candidate and genome wide association studies with Florida Native sheep have identified single nucleotide polymorphisms with additive and non-additive effects associated with parasite resistance. However, the role of other potential DNA variants, such as copy number variants (CNVs), controlling this complex trait have not been evaluated. The objective of the present study was to investigate the importance of CNVs on resistance to natural Haemonchus contortus infections in Florida Native sheep. A total of 200 sheep were evaluated in the present study. Phenotypic records included fecal egg count (FEC, eggs/gram), FAMACHA score, and packed cell volume (PCV, %). Sheep were genotyped using the GGP Ovine 50K SNP chip. The copy number analysis was used to identify CNVs using the univariate method. A total of 170 animals with CNVs and phenotypic data were used for the association testing. Association tests were carried out using single linear regression and Principal Component Analysis (PCA) correction to identify CNVs associated with FEC, FAMACHA, and PCV. To confirm our results, a second association testing using the correlation-trend test with PCA correction was performed. Significant CNVs were detected when their adjusted p-value was < 0.05 after FDR correction. A deletion CNV in chromosome 21 was associated with FEC. This DNA variant was located in intron 2 of RAB3IL gene and overlapped a QTL associated with changes in eosinophil number. Our study demonstrated for the first time that CNVs could be potentially involved with parasite resistance in this heritage sheep breed.

A de novo mosaic mutation in SPAST with two novel alternative alleles and chromosomal copy number variant in a boy with spastic paraplegia and autism spectrum disorder

2017 ◽  
Vol 60 (10) ◽  
pp. 548-552 ◽  
Author(s):  
A.M. Matthews ◽  
M. Tarailo-Graovac ◽  
E.M. Price ◽  
I. Blydt-Hansen ◽  
A. Ghani ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Spastic Paraplegia ◽  
Chromosomal Copy Number ◽  
Chromosomal Copy

Insights into the genomics of affective disorders

2020 ◽  
Vol 32 (1) ◽  
pp. 9-18
Author(s):  
Andreas J. Forstner ◽  
Per Hoffmann ◽  
Markus M. Nöthen ◽  
Sven Cichon
Keyword(s):  
Bipolar Disorder ◽  
Major Depression ◽  
Affective Disorders ◽  
Association Studies ◽  
Phenotypic Variability ◽  
Genetic Research ◽  
Autism Spectrum ◽  
Risk Scores ◽  
Depression Symptoms ◽  
Genome Wide Association Studies

Abstract Affective disorders, or mood disorders, are a group of neuropsychiatric illnesses that are characterized by a disturbance of mood or affect. Most genetic research in this field to date has focused on bipolar disorder and major depression. Symptoms of major depression include a depressed mood, reduced energy, and a loss of interest and enjoyment. Bipolar disorder is characterized by the occurrence of (hypo)manic episodes, which generally alternate with periods of depression. Formal and molecular genetic studies have demonstrated that affective disorders are multifactorial diseases, in which both genetic and environmental factors contribute to disease development. Twin and family studies have generated heritability estimates of 58–85 % for bipolar disorder and 40 % for major depression. Large genome-wide association studies have provided important insights into the genetics of affective disorders via the identification of a number of common genetic risk factors. Based on these studies, the estimated overall contribution of common variants to the phenotypic variability (single-nucleotide polymorphism [SNP]-based heritability) is 17–23 % for bipolar disorder and 9 % for major depression. Bioinformatic analyses suggest that the associated loci and implicated genes converge into specific pathways, including calcium signaling. Research suggests that rare copy number variants make a lower contribution to the development of affective disorders than to other psychiatric diseases, such as schizophrenia or the autism spectrum disorders, which would be compatible with their less pronounced negative impact on reproduction. However, the identification of rare sequence variants remains in its infancy, as available next-generation sequencing studies have been conducted in limited samples. Future research strategies will include the enlargement of genomic data sets via innovative recruitment strategies; functional analyses of known associated loci; and the development of new, etiologically based disease models. Researchers hope that deeper insights into the biological causes of affective disorders will eventually lead to improved diagnostics and disease prediction, as well as to the development of new preventative, diagnostic, and therapeutic strategies. Pharmacogenetics and the application of polygenic risk scores represent promising initial approaches to the future translation of genomic findings into psychiatric clinical practice.

scholarly journals Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Olafur O. Gudmundsson ◽  
G. Bragi Walters ◽  
Andres Ingason ◽  
Stefan Johansson ◽  
Tetyana Zayats ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variant ◽  
Pleiotropic Effect ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Hyperactivity Disorder

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

scholarly journals Currently Available Versions of Genome-Wide Association Studies Cannot Be Used to Query the Common Haptoglobin Copy Number Variant

2013 ◽  
Vol 62 (9) ◽  
pp. 860-861 ◽  
Author(s):  
Leah E. Cahill ◽  
Majken K. Jensen ◽  
Daniel I. Chasman ◽  
Aditi Hazra ◽  
Andrew P. Levy ◽  
...  
Keyword(s):  
Copy Number ◽  
Association Studies ◽  
Copy Number Variant ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
The Common

scholarly journals Characterisation of age and polarity at onset in bipolar disorder

2021 ◽  
pp. 1-11
Author(s):  
Janos L. Kalman ◽  
Loes M. Olde Loohuis ◽  
Annabel Vreeker ◽  
Andrew McQuillin ◽  
Eli A. Stahl ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Educational Attainment ◽  
Association Studies ◽  
Autism Spectrum ◽  
Screening Tools ◽  
Psychotic Symptoms ◽  
Significant Heterogeneity ◽  
Genome Wide Association Studies ◽  
Genetic Characteristics ◽  
Disease Characteristics

Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

scholarly journals Peruvian Newborn Male with 3p13 Deletion Syndrome Encompassing the FOXP1 Gene: Review of the Literature

2020 ◽  
Vol 09 (04) ◽  
pp. 270-278
Author(s):  
Hugo H. Abarca-Barriga ◽  
Milana Trubnykova ◽  
Félix Chavesta-Velásquez ◽  
Claudia Barletta-Carrillo ◽  
Marco Ordoñez-Linares ◽  
...  
Keyword(s):  
Copy Number ◽  
Choanal Atresia ◽  
Copy Number Variant ◽  
Autism Spectrum ◽  
Deletion Syndrome ◽  
Chromosomal Microarray ◽  
Facial Dysmorphism ◽  
Chromosomal Microarray Analysis ◽  
Heart Malformation ◽  
Number Variation

AbstractCopy number variation in loss of 3p13 is an infrequently reported entity characterized by hypertelorism, aniridia, microphthalmia, high palate, neurosensorial deafness, camptodactyly, heart malformation, development delay, autism spectrum disorder, seizures, and choanal atresia. The entity is caused probably by haploinsufficiency for FOXP1, UBA3, FAM19A1, and MITF. We report a newborn male with hypotonia, facial dysmorphism, heart malformation, and without clinical diagnosis; nevertheless, the use of appropriate genetic test, such us the chromosomal microarray analysis allowed identification of a copy number variant in loss of 5.5 Mb at chromosome 3 (p13-p14.1), that included 54 genes, encompassing FOXP1 gene. We compare the findings in our Peruvian patient to those of earlier reported patients; furthermore, add new signs for this entity.

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