Study Report

Basic Info
Reference |
Myles-Worsley, M., 2013 PMID: 23341099
|
Citation |
Myles-Worsley, M., et al. (2013). "Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family." Am J Med Genet B Neuropsychiatr Genet.
|
Disease Type |
Bipolar Disorder & Schizophrenia |
Study Design |
pedigree and case-control |
Study Type |
Candidate-gene CNV study |
Sample Size |
5-generation Palauan family, 21 family members, 790 controls |
SNP/Region/Marker Size |
1 CNV |
Predominant Ethnicity |
|

Detail Info
Sample Diagnosis |
research diagnostic criteria (RDC), DSM-IV criteria for adults, personal assistance and crisis evaluation (PACE) for adolescents. |
Sample Status |
Individuals identified by medical records or family referral as potentially affected with a psychotic disorder or prodromal symptoms were interviewed by an experienced clinician working with a Palauan mental health professional using a modified version of the schedule for affective disorders and schizophrenia (SADS)-lifetime version or the Kiddie-SADS in the case of adolescents. |
Technique |
We first used PCR-based methods to confirm the array-based CNV calls and test for the presence of the deletion in all 21 family members with a DNA sample, including the 7 subjects with Affymetrix 5.0 data and 14 additional family members, plus 10 unaffected reference subjects. Initially, all 31 subjects were tested using a set of four optimized real-time quantitative PCR (qPCR) primer pairs (P1L/R, P2L/R, P3L/R, and P4L/R) designed to amplify 70�133 bp sequences in regions upstream, downstream, and internal to the CNV. For more precise localization of the deletion, we first determined the approximate deletion end points using whole-genome nextgeneration sequencing (NGS) for one affected deletion-carrier, using Illumina Genome Network for shotgun sequencing. |
Statistical Method |
We first calculated a simple odds ratio, to determine the probability that the presence of the deletion was associated with psychotic disorders in Kindred 3501, regardless of inheritance patterns; Next, we conducted a pedigree-based association transmission test using the generalized disequilibriumtest (GDT). We then performed parametric linkage analysis using MENDEL 11.0. |
Result Summary |
Using an expanded sample of 21 family members, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three "obligate-carrier" parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the transcription start site, and the first 59 amino acids of the protein, including the first transmembrane Na(2+) /dicarboxylate symporter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. |

CNVs reported by this study for BD (count: 1)
Name |
Position |
Type |
Author Comments |
CNV_Myles-Worsley[2013]_1 |
chr9:4406529-4490826 |
deletion |
The deletion was not carried by the other 10 family members, 4 of whom were marry-in parents of psyc......
The deletion was not carried by the other 10 family members, 4 of whom were marry-in parents of psychosis patients, nor by the 10 reference DNA samples from control subjects not showing the CNV.
More...
|

Genes reported by this study for BD (count: 1)
Gene |
Statistical Values/Author Comments |
Result Category |
SLC1A1 |
Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an ......
Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders.
More...
|
Positive
|