Showing papers by "Jennifer L. Moran published in 2013"

Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Abstract: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-Analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case–control sample

Abstract: We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10−3 from the BD meta-analysis by Ferreira et al were genotyped We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=409 × 10−4) and 15q14 (rs2172835, P=0043) but not ANK3 (rs10994336, P=0912) We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis In addition, the combined analysis shows two novel GWS associations First, rs7296288 (P=897 × 10−9, odds ratio (OR)=09), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH Second, rs3818253 (P=388 × 10−8, OR=116), an intronic SNP on chromosome 20q112 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B

Association at SYNE1 in both bipolar disorder and recurrent major depression.

Abstract: Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10−7, odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10−8, OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.

Cis-Acting Regulation of Brain-Specific ANK3 Gene Expression by a Genetic Variant Associated with Bipolar Disorder

Abstract: Several genome-wide association studies (GWAS) for bipolar disorder (BD) have found a strong association of the Ankyrin3 (ANK3) gene. This association spans numerous linked single nucleotide polymorphisms (SNPs) in a ~250 kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as ankyrin-G (AnkG). Using RNA Ligase-Mediated Rapid Amplification of cDNA Ends (RLM-RACE) to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites (TSSs) and coupling of specific 5’ ends with 3’ mRNA splicing events in post-mortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD–associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 may be relevant to BD pathophysiology.

The genomic psychiatry cohort: Partners in discovery†‡

Abstract: The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.

Implication of a Rare Deletion at Distal 16p11.2 in Schizophrenia

Abstract: Context: Large genomic copy number variations have been implicated as strong risk factors for schizophrenia. However, the rarity of these events has created challenges for the identification of further pathogenic loci, and extremely large samples are required to provide convincing replication. Objective: To detect novel copy number variations that increase the susceptibility to schizophrenia by using 2 ethnically homogeneous discovery cohorts and replication in large samples. Design: Genetic association study of microarray data. Setting: Samples of DNA were collected at 9 sites from different countries. Participants: Two discovery cohorts consisted of 790 cases with schizophrenia and schizoaffective disorder and 1347 controls of Ashkenazi Jewish descent and 662 parent-offspring trios from Bulgaria, of which the offspring had schizophrenia or schizoaffective disorder. Replication data sets consisted of 12 398 cases and 17 945 controls. Main Outcome Measures: Statistically increased rate of specific copy number variations in cases vs controls. Results: One novel locus was implicated: a deletion at distal 16p11.2, which does not overlap the proximal 16p11.2 locus previously reported in schizophrenia and autism. Deletions at this locus were found in 13 of 13 850 cases (0.094%) and 3 of 19 954 controls (0.015%) (odds ratio, 6.25 [95% CI, 1.78-21.93]; P = .001, Fisher exact test). Conclusions: Deletions at distal 16p11.2 have been previously implicated in developmental delay and obesity. The region contains 9 genes, several of which are implicated in neurological diseases, regulation of body weight, and glucose homeostasis. A telomeric extension of the deletion, observed in about half the cases but no controls, potentially implicates an additional 8 genes. Our findings add a new locus to the list of copy number variations that increase the risk for development of schizophrenia. Uncovering the genetic factors underlying schizophrenia (SZ) has proven difficult despite heritability estimates of up to 80%.1 Copy number variations (CNVs) at several loci show consistently replicated evidence for association with SZ.2- 3 These CNVs are individually very rare, are not fully penetrant, and are found cumulatively in approximately 2% of SZ cases; therefore, large samples were required to establish their association. Given their low baseline frequency, further CNV susceptibility loci likely have yet to be discovered. In the present study, we report the identification of a CNV locus at distal 16p11.2 that increases the risk for SZ. Findings pointing to a possible association between this locus and SZ were obtained independently by 2 teams of investigators. During the process of obtaining replication data, the 2 groups became aware of each other's work and decided to combine results from their discovery and replication cohorts. Using high-resolution microarrays, one group (from New York and Israel) examined an SZ case-control cohort from the Ashkenazi Jewish (AJ) population, whereas the other group (from Cardiff, Wales) examined a cohort of parent-offspring trios from Bulgaria (BG). Because of the need for large-scale replication, we contacted research groups worldwide who were willing to share raw data from microarray-based CNV studies in cohorts of SZ cases and controls and obtained data from a total of approximately 34 000 individuals.

Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample.

Abstract: Detecting large copy number variants using exome genotyping arrays in a large Swedish schizophrenia sample

A genome wide survey supports the involvement of large copy number variants in schizophrenia with and without intellectual disability

Abstract: Copy number variants (CNVs) have been shown to play a role in schizophrenia and intellectual disability. We compared the CNV burden in 66 patients with intellectual disability and no symptoms of psychosis (ID-only) with the burden in 64 patients with intellectual disability and schizophrenia (ID + SCZ). Samples were genotyped on three plates by the Broad Institute using the Affymetrix 6.0 array. For CNVs larger than 100 kb, there was no difference in the CNV burden of ID-only and ID + SCZ. In contrast, the number of duplications larger than 1 Mb was increased in ID + SCZ compared to ID-only. We detected seven large duplications and two large deletions at chromosome 15q11.2 (18.5-20.1 Mb) which were all present in patients with ID + SCZ. The involvement of this region in schizophrenia was confirmed in Scottish samples from the ISC study (N = 2,114; 1,130 cases and 984 controls). Finally, one of the patients with schizophrenia and low IQ carrying a duplication at 15q11.2, is a member of a previously described pedigree with multiple cases of mild intellectual disability, schizophrenia, hearing impairment, retinitis pigmentosa and cataracts. DNA samples were available for 11 members of this family and the duplication was present in all 10 affected individuals and was absent in an unaffected individual. Duplications at 15q11.2 (18.5-20.1 Mb) are highly prevalent in a severe group of patients characterized by intellectual disability and comorbid schizophrenia. It is also associated with a phenotype that includes schizophrenia, low IQ, hearing and visual impairments resembling the spectrum of symptoms described in "ciliopathies."

Mosaic copy number variation in schizophrenia

Abstract: Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.

Residents examine factors associated with 30-day, same-cause hospital readmissions on an internal medicine service.

Abstract: In recent years, there has been increased interest in stemming the tide of hospital readmissions in an attempt to improve quality of care. This study presents the Phase I results of a resident-led quality improvement initiative to determine the percentage of and risk factors for same-cause readmissions (SCRs; defined as hospital readmission within 30 days of hospital discharge for treatment of the same condition) to the internal medicine service of a multispecialty teaching hospital in central Texas. Results indicate that patients diagnosed with chronic obstructive pulmonary disease/asthma or anemia may be at increased risk for SCRs. Those patients who are insured by Medicaid and those who require assistance from social services also demonstrated an increased risk for SCRs. This study appears to be the first resident-led initiative in the field to examine 30-day SCRs to an internal medicine service for demographic and clinical risk factors.