Genome wide association study identifies four loci for early onset schizophrenia

Abstract

Early onset schizophrenia (EOS, defined as first onset of schizophrenia before age 18) is a rare form of schizophrenia (SCZ). Though genome-wide association studies (GWASs) have identified multiple risk variants for SCZ, most of the cases included in these GWASs were not stratified according to their first age at onset. To date, the genetic architecture of EOS remains largely unknown. To identify the risk variants and to uncover the genetic basis of EOS, we conducted a two-stage GWAS of EOS in populations of Han Chinese ancestry in this study. We first performed a GWAS using 1,256 EOS cases and 2,661 healthy controls (referred as discovery stage). The genetic variants with a P < 1.0 × 10^-04 in discovery stage were replicated in an independent sample (903 EOS cases and 3,900 controls). We identified four genome-wide significant risk loci for EOS in the combined samples (2,159 EOS cases and 6,561 controls), including 1p36.22 (rs1801133, P_meta = 4.03 × 10^-15), 1p31.1 (rs1281571, P_meta = 4.14 × 10^-08), 3p21.31 (rs7626288, P_meta = 1.57 × 10^-09), and 9q33.3 (rs592927, P_meta = 4.01 × 10^-11). Polygenic risk scoring (PRS) analysis revealed substantial genetic overlap between EOS and SCZ. These discoveries shed light on the genetic basis of EOS. Further functional characterization of the identified risk variants and genes will help provide potential targets for therapeutics and diagnostics.

Fig. 1. Manhattan plot of EOS GWAS associations.

Associations were from the GWAS meta-analysis of the discovery stage (N = 1,256 EOS cases and 2,661 controls). The dashed black horizontal line indicates the suggestive P threshold (P < 1.0 × 10⁻⁰⁴). The genome-wide significant P threshold (P < 5.0 × 10⁻⁰⁸) is represented as the dashed red horizontal line. The arrows indicate the four genome-wide significant SNPs in our combined discovery and replication samples.

Fig. 2. Locuszoom plots of the genome-wide significant (LD independent) risk variants.

a rs1801133 is located in the fifth exon of MTHFR. b rs1281571 is located in the downstream of LPHN2. c rs7626288 is located in the intron 12 of LTF. d rs592927 is located in the upstream of RALGPS1.

Fig. 3. Genomic location of rs1801133 and the 3D structure of MTHFR.

a rs1801133 is located in the fifth exon of MTHFR. b rs1801133 is located in an evolutionary highly conserved genomic region. The amino acid encoded by rs1801133 was Ala in most of the species. However, a new amino acid (Val) has emerged in humans. c The 3D structure of MTHFR with different amino acids at rs1801133.

Fig. 4. Genetic risk prediction accuracy in subgroup 1 EOS cases and controls (discovery stage) using different training sets.

PRSs were computed using GWAS summary statistics from three training sets. The red plot represents PRS result from EAS training set (including 22,778 SCZ cases and 35,362 controls). The green plot represents PRS result from CLOZUK + PGC2 training set (including 40,675 SCZ cases and 64,643 controls). The blue plot represents PRS result from Chinese+PGC2 training set (including 43,175 SCZ cases and 65,166 controls).