title: Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample.
abstract: A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores-using single nucleotide polymorphism (SNP) information of SCZ GWAS-(polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample.
authors.affiliation: 1] Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany [2] DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany [3] Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Papiol
authors.affiliation: 1] Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany [2] Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM), Barcelona, Spain [3] Unitat Antropologia, Departament de Biologia Animal, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Mitjans
authors.affiliation: Fondazione Santa Lucia, Laboratorio di Neuropsichiatria, Roma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Assogna
authors.affiliation: Fondazione Santa Lucia, Laboratorio di Neuropsichiatria, Roma, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piras
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Hammer
authors.affiliation: Department of Neuroscience, IRCCS Fondazione Santa Lucia and Tor Vergata University, Roma, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Caltagirone
authors.affiliation: 1] Centro de Investigaciones Biomédicas en Red de Salud Mental (CIBERSAM), Barcelona, Spain [2] Unitat Antropologia, Departament de Biologia Animal, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Arias
authors.affiliation: 1] Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany [2] DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Fondazione Santa Lucia, Laboratorio di Neuropsichiatria, Roma, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Spalletta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000033:anatomy & histology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D066128:Gray Matter / Q000033:anatomy & histology; D006801:Humans; D007558:Italy; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D066127:White Matter / Q000033:anatomy & histology; D055815:Young Adult