Dataset Information

Examining the role of common and rare mitochondrial variants in schizophrenia.

ABSTRACT: Oxidative phosphorylation within mitochondria is the main source of aerobic energy for neuronal functioning, and the key genes are located in mitochondrial DNA. Deficits in oxidative phosphorylation functioning have been reported for schizophrenia, but efforts in the identification of genetic markers within the mitochondrial DNA that predispose to schizophrenia have been limited. We genotyped a set of mitochondrial SNPs using Illumina HumanExome arrays and tested for association in the Swedish schizophrenia sample (N> 10,000). We developed a novel approach for mitochondrial DNA imputation in order to increase the number of common SNPs available for association analysis. The most significant findings were for the mitochondrial SNPs C15452A (GRCh38.p10; rs527236209; p = 0.007; gene MT-CYB; defining haplogroup JT); A11251G (rs869096886; p = 0.007; gene MT-ND4; defining haplogroup JT), and T4216C (rs1599988; p = 0.008, gene MT-ND1, defining haplogroup R2'JT). We also conducted rare variant burden analyses and obtained a p-value of 0.007. For multimarker haplotypes analysis, the most significant finding was for the J group (OR: 0.86, p = 0.02). We conducted the largest association study of mitochondrial DNA variants and schizophrenia but did not find an association that survived multiple testing correction. Analysis of a larger sample is required and will allow a better understanding of the role of mitochondria in schizophrenia.

SUBMITTER: Goncalves VF

PROVIDER: S-EPMC5784966 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Examining the role of common and rare mitochondrial variants in schizophrenia.

Gonçalves Vanessa F VF Giamberardino Stephanie N SN Crowley James J JJ Vawter Marquis P MP Saxena Richa R Bulik Cynthia M CM Yilmaz Zeynep Z Hultman Christina M CM Sklar Pamela P Kennedy James L JL Sullivan Patrick F PF Knight Jo J

PloS one 20180125 1

Oxidative phosphorylation within mitochondria is the main source of aerobic energy for neuronal functioning, and the key genes are located in mitochondrial DNA. Deficits in oxidative phosphorylation functioning have been reported for schizophrenia, but efforts in the identification of genetic markers within the mitochondrial DNA that predispose to schizophrenia have been limited. We genotyped a set of mitochondrial SNPs using Illumina HumanExome arrays and tested for association in the Swedish s ...[more]

PMID: 29370225

Similar Datasets

Project description:Abstract Schizophrenia (SZ) is a debilitating psychiatric disorder for which the complex genetic mechanisms underlying the disease state remain unclear. Whereas highly penetrant variants have proven well-suited to human induced pluripotent stem cell (hiPSC)-based models, the power of hiPSC-based studies to resolve the much smaller effects of common variants within the size of cohorts that can be realistically assembled remains uncertain. Overall, we consider the successes and limitations in applying human induced pluripotent stem cell (hiPSC)-based models to study the impact of rare and common variants in SZ risk. To explore the neuronal impact of rare variants, we investigated the relationship between heterozygous 2p16.3 deletions, alternative splicing of NRXN1, and perturbations in neuronal activity, finding some commonalities with idiopathic SZ. We identified ~100 NRXN1α isoforms in control hiPSC neurons; patient-derived 2p16.3 neurons show perturbed NRXN1 isoform repertoires, reduced neuronal branching and decreased neuronal activity, which unexpectedly can be partially ameliorated by overexpression of a single NRXN1 isoform. Second, we present a genetics-driven hiPSC-based CRISPR-mediated approach for the functional validation of common variants and genes associated with SZ, evaluating the impact of one putative causal SZ SNP (FURIN rs4702) and two SZ-associated genes (SNAP91 and TSNARE1) on global gene expression patterns and synaptic function. We predict a growing convergence between hiPSC and post-mortem studies as both approaches expand to larger cohort sizes. We demonstrate a systematic and scalable strategy to interpret and evaluate the growing number of SZ-associated variants and genes across neural cell types and genetic backgrounds. Altogether, our objective is to dissect the genetic origins of SZ while developing a precision medicine approach to screen for novel therapeutics with which to prevent or reverse disease course. Concurrent Symposia

Dataset Information

Examining the role of common and rare mitochondrial variants in schizophrenia.

Publications

Examining the role of common and rare mitochondrial variants in schizophrenia.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets