Two non-synonymous markers in PTPN21, identified by genome-wide association study data-mining and replication, are associated with schizophrenia

Abstract

We conducted data-mining analyses of genome wide association (GWA) studies of the CATIE and MGS-GAIN datasets, and found 13 markers in the two physically linked genes, PTPN21 and EML5, showing nominally significant association with schizophrenia. Linkage disequilibrium (LD) analysis indicated that all 7 markers from PTPN21 shared high LD (r2>0.8), including rs2274736 and rs2401751, the two non-synonymous markers with the most significant association signals (rs2401751, P=1.10×10−3 and rs2274736, P=1.21×10−3). In a meta-analysis of all 13 replication datasets with a total of 13,940 subjects, we found that the two non-synonymous markers are significantly associated with schizophrenia (rs2274736, OR=0.92, 95% CI: 0.86–0.97, P=5.45×10−3 and rs2401751, OR = 0.92, 95% CI: 0.86–0.97, P=5.29×10−3). One SNP (rs7147796) in EML5 is also significantly associated with the disease (OR = 1.08, 95% CI: 1.02-1.14, P=6.43×10−3). These 3 markers remain significant after Bonferroni correction. Furthermore, haplotype conditioned analyses indicated that the association signals observed between rs2274736/rs2401751 and rs7147796 are statistically independent. Given the results that 2 non-synonymous markers in PTPN21 are associated with schizophrenia, further investigation of this locus is warranted.

Looking for Sunshine: Genetic Predisposition to Sun Seeking in 265,000 Individuals of European Ancestry

“…Four of these genes are located in two genome-wide-significant regions identified in our GWAS meta-analysis (CADM2, MTMR2/CEP57/FAM76B). The additional genes are also related to neuropsychological traits, such as cognitive function (CAMKV, ARHGAP15, SPATA, and SNX29), intelligence (CAMKV, ARGHAP15, and SNX29), educational attainment (SNX29 and CAMKV), general risk tolerance (BLK), being a morning person (CAMKV, ARGHAP15, and RNF123), feeling fed up (RNF123), worry (MCHR1), and schizophrenia (PTPN21) (Chen et al, 2011;Davies et al, 2018Davies et al, , 2016Davies et al, , 2015Jones et al, 2019;Karlsson Linnér et al, 2019;Lee et al, 2018;Luciano et al, 2018;Nagel et al, 2018a;2018b;Okbay et al, 2016;Savage et al, 2018). Building on the gene-based analyses, we performed gene-set enrichment analyses, with no statistically significant result.…”

The genomic psychiatry cohort: Partners in discovery

“…These findings were rapidly replicated in other studies (Stefansson et al, 2008; Stefansson et al, 2009; Shi et al, 2009). Our group has continued to extend these findings in a number of follow-up publications (Ng et al, 2009; O’Dushlaine et al, 2011; Gilks et al, 2010; Moskvina et al, 2010; Chen et al, 2011; Raychaudhuri et al, 2010; Pato et al, 2010; Bridges et al, 2011; Chen et al, 2011; Sullivan et al, 2012; Jia et al, 2012a,b; Fanous et al, 2012a,b; Keller et al, 2012; Derks et al, 2012; Richards et al, 2012; Bigdeli et al, 2013). …”

Selection signatures of Fuzhong Buffalo based on whole-genome sequences

“…ADGRL3 was associated with attention-deficit/hyperactivity disorder [ 53 ]. PTPN21 (protein tyrosine phosphatase, non-receptor type 21), a protein-coding gene which can positively influence cortical neuronal survival and enhance neuritic length [ 54 ], was identified as a potential risk gene for schizophrenia [ 55 ], showing a reduction in nucleotide diversity in FZ buffalo (Fig. 3 c).…”