A population-specific uncommon variant in GRIN3A associated with schizophrenia

Background: Genome-wide association studies have successfully identified several common variants showing robust association with schizophrenia. However, individually, these variants only produce a weak effect. To identify genetic variants with larger effect sizes, increasing attention is now being paid to uncommon and rare variants. Methods: From the 1000 Genomes Project data, we selected 47 candidate single nucleotide variants (SNVs), which were: 1) uncommon (minor allele frequency<5%); 2) Asian-specific; 3) missense, nonsense, or splice site variants predicted to be damaging; and 4) located in candidate genes for schizophrenia and bipolar disorder. We examined their association with schizophrenia, using a Japanese case-control cohort (2012 cases and 2781 control subjects). Additional meta-analysis was performed using genotyping data from independent Han-Chinese case-control (333 cases and 369 control subjects) and family samples (9 trios and 284 quads). Results: We identified disease association of a missense variant in GRIN3A (p.R480G, rs149729514, p =.00042, odds ratio [OR] = 1.58), encoding a subunit of the N-methyl-D-aspartate type glutamate receptor, with study-wide significance (threshold p =.0012). This association was supported by meta-analysis (combined p = 3.3×10 ^-5, OR = 1.61). Nominally significant association was observed in missense variants from FAAH, DNMT1, MYO18B, and CFB, with ORs of risk alleles ranging from 1.41 to 2.35. Conclusions: The identified SNVs, particularly the GRIN3A R480G variant, are good candidates for further replication studies and functional evaluation. The results of this study indicate that association analyses focusing on uncommon and rare SNVs are a promising way to discover risk variants with larger effects.