title: Cumulative genetic risk and prefrontal activity in patients with schizophrenia.
abstract: The lack of consistency of genetic associations in highly heritable mental illnesses, such as schizophrenia, remains a challenge in molecular psychiatry. Because clinical phenotypes for psychiatric disorders are often ill defined, considerable effort has been made to relate genetic polymorphisms to underlying physiological aspects of schizophrenia (so called intermediate phenotypes), that may be more reliable. Given the polygenic etiology of schizophrenia, the aim of this work was to form a measure of cumulative genetic risk and study its effect on neural activity during working memory (WM) using functional magnetic resonance imaging. Neural activity during the Sternberg Item Recognition Paradigm was measured in 79 schizophrenia patients and 99 healthy controls. Participants were genotyped, and a genetic risk score (GRS), which combined the additive effects of 41 single-nucleotide polymorphisms (SNPs) from 34 risk genes for schizophrenia, was calculated. These risk SNPs were chosen according to the continuously updated meta-analysis of genetic studies on schizophrenia available at www.schizophreniaresearchforum.org. We found a positive relationship between GRS and left dorsolateral prefrontal cortex inefficiency during WM processing. GRS was not correlated with age, performance, intelligence, or medication effects and did not differ between acquisition sites, gender, or diagnostic groups. Our study suggests that cumulative genetic risk, combining the impact of many genes with small effects, is associated with a known brain-based intermediate phenotype for schizophrenia. The GRS approach could provide an advantage over studying single genes in studies focusing on the genetic basis of polygenic conditions such as neuropsychiatric disorders.
authors.affiliation: MGH/MIT/HMS Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Walton
authors.forename: Jessica
authors.initials: J
authors.lastname: Turner
authors.forename: Randy L
authors.initials: RL
authors.lastname: Gollub
authors.forename: Dara S
authors.initials: DS
authors.lastname: Manoach
authors.forename: Anastasia
authors.initials: A
authors.lastname: Yendiki
authors.forename: Beng-Choon
authors.initials: BC
authors.lastname: Ho
authors.forename: Scott R
authors.initials: SR
authors.lastname: Sponheim
authors.forename: Vince D
authors.initials: VD
authors.lastname: Calhoun
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrlich
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D059907:Functional Neuroimaging; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult