title: A double amino-acid change in the HLA-A peptide-binding groove is associated with response to psychotropic treatment in patients with schizophrenia.
abstract: The choice of an efficient psychotropic treatment for patients with schizophrenia is a key issue to improve prognosis and quality of life and to decrease the related burden and costs. As for other complex disorders, response to drugs in schizophrenia is highly heterogeneous and the underlying molecular mechanisms of this diversity are still poorly understood. In a carefully followed-up cohort of schizophrenic patients prospectively treated with risperidone or olanzapine, we used a specially designed single-nucleotide polymorphism (SNP) array to perform a large-scale genomic analysis and identify genetic variants associated with response to psychotropic drugs. We found significant associations between response to treatment defined by the reduction in psychotic symptomatology 42 days after the beginning of treatment and SNPs located in the chromosome 6, which houses the human leukocyte antigen (HLA). After imputation of the conventional HLA class I and class II alleles, as well as the amino-acid variants, we observed a striking association between a better response to treatment and a double amino-acid variant at positions 62 and 66 of the peptide-binding groove of the HLA-A molecule. These results support the current notion that schizophrenia may have immune-inflammatory underpinnings and may contribute to pave the way for personalized treatments in schizophrenia.
authors.affiliation: 201;quipe EA4627, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Le Clerc
authors.affiliation: 201;quipe EA4627, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Taing
authors.affiliation: 1] INSERM, U955, Psychiatrie Génétique, Créteil, France [2] Université Paris-Est, Faculté de Médecine, Créteil, France [3] AP-HP, DHU PePSY, Pôle de Psychiatrie, Hôpitaux Universitaires Henri Mondor, Créteil, France [4] Fondation FondaMental, Créteil, France.
authors.forename: G
authors.initials: G
authors.lastname: Fond
authors.affiliation: 1] INSERM, U955, Psychiatrie Génétique, Créteil, France [2] Université Paris-Est, Faculté de Médecine, Créteil, France [3] AP-HP, DHU PePSY, Pôle de Psychiatrie, Hôpitaux Universitaires Henri Mondor, Créteil, France [4] Fondation FondaMental, Créteil, France.
authors.forename: A
authors.initials: A
authors.lastname: Meary
authors.affiliation: 1] Fondation FondaMental, Créteil, France [2] Service de Psychiatrie Adulte, Hôpital Gabriel Montpied, Clermont-Ferrand, France.
authors.forename: P-M
authors.initials: PM
authors.lastname: Llorca
authors.affiliation: 1] Fondation FondaMental, Créteil, France [2] Service de Psychiatrie Adulte, Hôpital Gabriel Montpied, Clermont-Ferrand, France.
authors.forename: O
authors.initials: O
authors.lastname: Blanc
authors.affiliation: INSERM, U775, Centre de recherches Biomédicales, Université Paris Descartes, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Beaune
authors.affiliation: INSERM, U955, Psychiatrie Génétique, Créteil, France.
authors.forename: K
authors.initials: K
authors.lastname: Rajagopal
authors.affiliation: 1] INSERM, U955, Psychiatrie Génétique, Créteil, France [2] Université Paris-Est, Faculté de Médecine, Créteil, France [3] Fondation FondaMental, Créteil, France.
authors.forename: S
authors.initials: S
authors.lastname: Jamain
authors.affiliation: 1] Laboratoire Jean Dausset (LabEx Transplantex) et INSERM, U1160, Hôpital Saint Louis, Paris, France [2] Université Paris Diderot, Sorbonne Paris-Cité, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Tamouza
authors.affiliation: 201;quipe EA4627, Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France.
authors.forename: J-F
authors.initials: JF
authors.lastname: Zagury
authors.affiliation: 1] INSERM, U955, Psychiatrie Génétique, Créteil, France [2] Université Paris-Est, Faculté de Médecine, Créteil, France [3] AP-HP, DHU PePSY, Pôle de Psychiatrie, Hôpitaux Universitaires Henri Mondor, Créteil, France [4] Fondation FondaMental, Créteil, France.
authors.forename: M
authors.initials: M
authors.lastname: Leboyer
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D005260:Female; D015234:HLA-A Antigens / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D000077152:Olanzapine; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018967:Risperidone / Q000627:therapeutic use*; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D015234:HLA-A Antigens; D001569:Benzodiazepines; D018967:Risperidone; D000077152:Olanzapine