Polygenic risk for schizophrenia associated with working memory-related prefrontal brain activation in patients with schizophrenia and healthy controls.
Schizophrenia is a highly heritable and polygenic disease, and identified common genetic variants have shown weak individual effects. Many studies have reported altered working memory (WM)-related brain activation in schizophrenia, preferentially in the frontal lobe. Such differences in brain activations could reflect inherited alterations possibly involved in the disease etiology, or rather secondary disease-related mechanisms. The use of polygenic risk scores (PGRS) based on a large number of risk polymorphisms with small effects is a valuable approach to examine the effect of cumulative genetic risk on brain functioning. This study examined the impact of cumulative genetic risk for schizophrenia on WM-related brain activations, assessed with functional magnetic resonance imaging. For each participant (63 schizophrenia patients and 118 healthy controls), we calculated a PGRS for schizophrenia based on 18 862 single-nucleotide polymorphism in a large multicenter genome-wide association study including 9146 schizophrenia patients and 12 111 controls, performed by the Psychiatric Genomics Consortium. As expected, the PGRS was significantly higher in patients compared with healthy controls. Further, the PGRS was related to differences in frontal lobe brain activation between high and low WM demand. Specifically, even in absence of main effects of diagnosis, increased PGRS was associated with decreased activation difference in the right middle-superior prefrontal cortex (BA 10/11) and the right inferior frontal gyrus (BA 45). This effect was seen in both cases and controls, and was not influenced by sex, age, or task performance. The findings support the notion of dysregulation of frontal lobe functioning as an inherited vulnerability factor in schizophrenia.
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; karolina.kauppi@medisin.uio.no.
Karolina
K
Kauppi
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway;
Lars T
LT
Westlye
Martin
M
Tesli
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
Francesco
F
Bettella
Christine L
CL
Brandt
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
Morten
M
Mattingsdal
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway;
Torill
T
Ueland
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Department of Psychology, University of Oslo, Oslo, Norway;
Thomas
T
Espeseth
Norwegian Center for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Diakonhjemmet Hospital, Oslo, Norway;
Ingrid
I
Agartz
Ingrid
I
Melle
Division of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Srdjan
S
Djurovic
Ole A
OA
Andreassen
D000328:Adult; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008875:Middle Aged; D020412:Multifactorial Inheritance; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012306:Risk; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*
fMRI; polygenic; schizophrenia