Table 1.
LoF and damaging missense variants identified in the discovery and replication phases as significantly associated with disease risk. Variant location, type of variant, MAF and allele counts for affected cases, controls and population controls (ExAC cohort), diseases diagnosis, p-values for association and Odds Ratios are presented. Abbreviations: ASD, Autism spectrum disorder; ExAC, Exome Aggregation Consortium; ct, (allele) count; Diag, diagnosis; Gen ct, genotype count; ID, intellectual disability; Inf, infinity; MAF, Minor Allele Frequency; Mis, missense variant; Non, nonsense mutation; OR, Odds Ratio; PSC, premature start codon gain; Scz, schizophrenia; Scz-ID, dual diagnosis of schizophrenia and ID; SpA, splice acceptor variant; SpI, splice intronic variant.
| Gene | cDNA | Type | MAF cases (Gen ct) | Diag | MAF con (Gen ct) | P value | OR (CI) | MAF ExAC |
|---|---|---|---|---|---|---|---|---|
| FIRST DISCOVERY PHASE | ||||||||
| GRIK1 | c.1232 T > A (p.Leu411*) | Non | 3.03 × 10−4 (1 T/A) | Scz-ID | Inf | 5.78 × 10−5 | ||
| GRIK3 | c.928 T > G (p.Ser310Ala) | Mis | 0.17 (451 T/G, 51 G/G) | All | 0.25 (846 T/G, 113 G/G) | 1.01 × 10−18 | 0.59 (0.52–0.66) | 0.27 |
| GRIK3 | c.1756T > G (p.Phe586Val) | Mis | 0.003 (9 T/G) | ASD | 2.84 × 10−7 | Inf | Novel | |
| GRIK4 | c.293 C > A (p.Ser98*) | Non | 3.03 × 10−4 (1 C/A) | ID | Inf | Novel | ||
| GRIK5 | c.2542 C > T (p.Gln848*) | Non | 3.03 × 10−4 (1 C/T) | ASD | Inf | Novel | ||
| GRIK5 | c.2684 C > G (p.Ala895Gly) | Mis | 0.005 (9 C/G, 4 G/G) | Scz | 4.06 × 10−5 | 44.83 (2.70–765) | Novel | |
| GRIK5 | c.1270-1 G > T | SpA | 3.03 × 10−4 (1 G/T) | ASD | Inf | Novel | ||
| NETO1 | c.-143G > T | PSC | 3.03 × 10−4 (1 G/T) | ASD | Inf | Novel | ||
| SECOND DISCOVERY PHASE | ||||||||
| GRIK2 | c.1525–10 C > T | SpI | 0.010 (16 C/T) | Scz | 4.43 × 10−8 | 42.26 (2.53–704) | Novel | |
| GRIK3 | c.2593 A > G (p.Arg865Gly) | Mis | 0.008 (14 A/G) | Scz | 6.81 × 10−6 | 73 (4–1226) | 0.005 | |
| MAF (ct) Cases | MAF (ct) Con ExAC | P value | OR (CI) | |||||
| ExAC REPLICATION FOLLOW UP (1) | ||||||||
| GRIK1 | c.2705 T > C (p.Leu902Ser) | Mis | 0.031 (101/3,288) | 0.08 (68,18/90,756) | 4.83 × 10−15 | 0.399 (0.320–0.476) | ||
| GRIK3 | c.928 T > G (p.Ser310Ala) | Mis | 0.168 (553/3,288) | 0.29 (25,607/90,756) | 6.49 × 10−50 | 0.513 (0.469–0.564) | ||
| GRIK5 | c.2684 C > G (p.Ala895Gly) | Mis | 0.005 (17/3,288) | 0.00 (0/90,756) | 8.55 × 10−24 | Inf | ||
| MAF (ct) Psy ExAC | MAF (ct) Con ExAC | P value | OR (CI) | |||||
| ExAC REPLICATION FOLLOW-UP (2) | ||||||||
| GRIK1 | c.2705 T > C (p.Leu902Ser) | Mis | 0.040 (1,155/30,000) | 0.075 (6,818/90,756) | 1.145 × 10−108 | 0.49 (0.46–0.53) | ||
| GRIK3 | c.928 T > G (p.Ser310Ala) | Mis | 0.245 (7,364/30,000) | 0.29 (25,607/90,756) | 4.076 × 10−35 | 0.81 (0.80–0.84) | ||
| GRIK4 | c.1582 G > A (p.Val528Ile) | Mis | 0.0002 (5/30,000) | 0.011 (1,028/90,756) | 5.467 × 10−74 | 0.01 (0.004–0.03) | ||
| NETO1 | c.1460 C > G (p.Ala487Gly) | Mis | 6.60 × 10−5 (2/30,000) | 0.008 (704/90,756) | 7.967 × 10−52 | 0.009 (0.001–0.03) | ||
| NETO2 | c.1366 T > A (p.Ser456Thr) | Mis | 6.60 × 10−5 (2/30,000) | 0.009 (808/90,756) | 2.056 × 10−59 | 0.007 (0.001–0.02) | ||