The heritable component of schizophrenia (SCH) as a polygenic trait is represented by numerous variants from a heterogeneous group of genes each contributing a relatively small effect. Various SNPs have already been found and analyzed in genes encoding the NMDAR subunits. However, less is known about genetic variations of genes encoding the AMPA and kainate receptor subunits. We analyzed sixteen iGluR genes in full length to determine the sequence variability of iGluR genes. Our aim was to describe the rate of genetic variability, its distribution, and the co-occurrence of variants and to identify new candidate risk variants or haplotypes. The cumulative effect of genetic risk was then estimated using a simple scoring model. GRIN2A-B, GRIN3A-B, and GRIK4 genes showed significantly increased genetic variation in SCH patients. The fixation index statistic revealed eight intronic haplotypes and an additional four intronic SNPs within the sequences of iGluR genes associated with SCH (p < 0.05). The haplotypes were used in the proposed simple scoring model and moreover as a test for genetic predisposition to schizophrenia. The positive likelihood ratio for the scoring model test reached 7.11. We also observed 41 protein-altering variants (38 missense variants, four frameshifts, and one nonsense variant) that were not significantly associated with SCH. Our data suggest that some intronic regulatory regions of iGluR genes and their common variability are among the components from which the genetic predisposition to SCH is composed.

Faculty of Science Charles University 12800 Prague Czech Republic

Genomics Core Facility EMBL 69117 Heidelberg Germany

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University 12800 Prague Czech Republic

Institute of Biotechnology Czech Academy of Sciences BIOCEV 25250 Vestec Czech Republic

Institute of Physiology Czech Academy of Sciences 14220 Prague Czech Republic

Institute of Physiology Czech Academy of Sciences BIOCEV 25250 Vestec Czech Republic

The National Institute of Mental Health 25067 Klecany Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc22001218

003      

CZ-PrNML

005      

20220112153531.0

007      

ta

008      

220107s2021 sz f 000 0|eng||

009      

AR

024    7_

$a 10.3390/jpm11121250 $2 doi

035    __

$a (PubMed)34945722

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a sz

100    1_

$a Hirschfeldova, Katerina $u Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 12800 Prague, Czech Republic $u Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic

245    10

$a Evidence for the Association between the Intronic Haplotypes of Ionotropic Glutamate Receptors and First-Episode Schizophrenia / $c K. Hirschfeldova, J. Cerny, P. Bozikova, V. Kuchtiak, T. Rausch, V. Benes, F. Spaniel, D. Gregus, J. Horacek, L. Vyklicky, A. Balik

520    9_

$a The heritable component of schizophrenia (SCH) as a polygenic trait is represented by numerous variants from a heterogeneous group of genes each contributing a relatively small effect. Various SNPs have already been found and analyzed in genes encoding the NMDAR subunits. However, less is known about genetic variations of genes encoding the AMPA and kainate receptor subunits. We analyzed sixteen iGluR genes in full length to determine the sequence variability of iGluR genes. Our aim was to describe the rate of genetic variability, its distribution, and the co-occurrence of variants and to identify new candidate risk variants or haplotypes. The cumulative effect of genetic risk was then estimated using a simple scoring model. GRIN2A-B, GRIN3A-B, and GRIK4 genes showed significantly increased genetic variation in SCH patients. The fixation index statistic revealed eight intronic haplotypes and an additional four intronic SNPs within the sequences of iGluR genes associated with SCH (p < 0.05). The haplotypes were used in the proposed simple scoring model and moreover as a test for genetic predisposition to schizophrenia. The positive likelihood ratio for the scoring model test reached 7.11. We also observed 41 protein-altering variants (38 missense variants, four frameshifts, and one nonsense variant) that were not significantly associated with SCH. Our data suggest that some intronic regulatory regions of iGluR genes and their common variability are among the components from which the genetic predisposition to SCH is composed.

655    _2

$a časopisecké články $7 D016428

700    1_

$a Cerny, Jiri $u Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, 25250 Vestec, Czech Republic

700    1_

$a Bozikova, Paulina $u Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, 25250 Vestec, Czech Republic

700    1_

$a Kuchtiak, Viktor $u Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic $u Faculty of Science, Charles University, 12800 Prague, Czech Republic

700    1_

$a Rausch, Tobias $u Genomics Core Facility, EMBL, 69117 Heidelberg, Germany

700    1_

$a Benes, Vladimir $u Genomics Core Facility, EMBL, 69117 Heidelberg, Germany

700    1_

$a Spaniel, Filip $u The National Institute of Mental Health, 25067 Klecany, Czech Republic

700    1_

$a Gregus, David $u The National Institute of Mental Health, 25067 Klecany, Czech Republic

700    1_

$a Horacek, Jiri $u The National Institute of Mental Health, 25067 Klecany, Czech Republic

700    1_

$a Vyklicky, Ladislav $u Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic

700    1_

$a Balik, Ales $u Institute of Physiology, Czech Academy of Sciences, 14220 Prague, Czech Republic $u Institute of Physiology, Czech Academy of Sciences, BIOCEV, 25250 Vestec, Czech Republic

773    0_

$w MED00203320 $t Journal of personalized medicine $x 2075-4426 $g Roč. 11, č. 12 (2021)

856    41

$u https://pubmed.ncbi.nlm.nih.gov/34945722 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y - $z 0

990    __

$a 20220107 $b ABA008

991    __

$a 20220112153527 $b ABA008

999    __

$a ind $b bmc $g 1745406 $s 1152365

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2021 $b 11 $c 12 $e 20211125 $i 2075-4426 $m Journal of personalized medicine $n J. pers. med. $x MED00203320

GRA    __

$a LTAUSA19122 $p Ministerstvo Školství, Mládeže a Tělovýchovy

GRA    __

$a 20-179458 $p Grantová Agentura České Republiky

GRA    __

$a TN01000013 $p Technologická Agentura České Republiky

GRA    __

$a CZ.02.1.01/0.0/0.0/16_025/0007444 $p Ministerstvo Školství, Mládeže a Tělovýchovy

GRA    __

$a 1206218 $p Grantová Agentura, Univerzita Karlova

GRA    __

$a NU21-04-00405 $p Agentura Pro Zdravotnický Výzkum České Republiky

LZP    __

$a Pubmed-20220107