TY - JOUR
T1 - Genetic neuropathology of schizophrenia
T2 - New approaches to an old question and new uses for postmortem human brains
AU - Kleinman, Joel E.
AU - Law, Amanda J.
AU - Lipska, Barbara K.
AU - Hyde, Thomas M.
AU - Ellis, Justin K.
AU - Harrison, Paul J.
AU - Weinberger, Daniel R.
N1 - Funding Information:
This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health . PJH receives grant support from the Medical Research Council , Wellcome Trust , and Stanley Medical Research Institute .
PY - 2011/1/15
Y1 - 2011/1/15
N2 - Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and control subjects but is potentially confounded by a number of artifacts, including medication, substance misuse, and other secondary effects of illness. Genetic advances now make possible a novel approach that focuses on how allelic variation in risk-associated genes affects expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances, expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia and probably other neurodevelopmental disorders as well. Studies of this kind can provide clues as to the biological mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself.
AB - Human postmortem brain studies are critical for elucidating the pathophysiology and etiology of schizophrenia and other major mental illnesses. The traditional approach compares patients and control subjects but is potentially confounded by a number of artifacts, including medication, substance misuse, and other secondary effects of illness. Genetic advances now make possible a novel approach that focuses on how allelic variation in risk-associated genes affects expression and function of transcripts and proteins. These questions can be addressed in normal brain, overcoming to some extent the confounding effects of studying brains from subjects with schizophrenia; equally, extension of the studies to include cases also has advantages. Conceptually, the approach may be seen as the neuropathologic counterpart of genetic neuroimaging, representing a potentially powerful intermediate phenotype. For several schizophrenia susceptibility genes, the data show that risk-associated polymorphisms do affect gene expression or the function of the encoded protein; in some instances, expression of downstream or interacting partners of the gene are also altered. A further striking finding is that the implicated transcripts often appear to be enriched in, or specific to, human brain. Some also show enhanced expression in fetal brain. These considerations give unique importance to postmortem human brain tissue in elucidating the genetic mechanisms underlying schizophrenia and probably other neurodevelopmental disorders as well. Studies of this kind can provide clues as to the biological mechanisms of genetic association, especially when carried out in conjunction with experimental studies. Moreover, the data, interpreted judiciously, can strengthen the plausibility of the association itself.
KW - Alternative splicing
KW - gene expression
KW - genetics
KW - human brain
KW - neuropathology
KW - schizophrenia
UR - http://www.scopus.com/inward/record.url?scp=78650443750&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78650443750&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2010.10.032
DO - 10.1016/j.biopsych.2010.10.032
M3 - Review article
C2 - 21183009
AN - SCOPUS:78650443750
SN - 0006-3223
VL - 69
SP - 140
EP - 145
JO - Biological psychiatry
JF - Biological psychiatry
IS - 2
ER -