Evidence for X-chromosomal schizophrenia associated with microRNA alterations.
BACKGROUND
Schizophrenia is a severe disabling brain disease affecting about 1% of the population. Individual microRNAs (miRNAs) affect moderate downregulation of gene expression. In addition, components required for miRNA processing and/or function have also been implicated in X-linked mental retardation, neurological and neoplastic diseases, pointing to the wide ranging involvement of miRNAs in disease.


RESULTS
To explore the role of miRNAs in schizophrenia, 59 microRNA genes on the X-chromosome were amplified and sequenced in males with (193) and without (191) schizophrenia spectrum disorders to test the hypothesis that ultra-rare mutations in microRNA collectively contribute to the risk of schizophrenia. Here we provide the first association of microRNA gene dysfunction with schizophrenia. Eight ultra-rare variants in the precursor or mature miRNA were identified in eight distinct miRNA genes in 4% of analyzed males with schizophrenia. One ultra-rare variant was identified in a control sample (with a history of depression) (8/193 versus 1/191, p = 0.02 by one-sided Fisher's exact test, odds ratio = 8.2). These variants were not found in an additional 7,197 control X-chromosomes.


CONCLUSIONS
Functional analyses of ectopically expressed copies of the variant miRNA precursors demonstrate loss of function, gain of function or altered expression levels. While confirmation is required, this study suggests that microRNA mutations can contribute to schizophrenia.
Feng
Jinong
J
Division of Molecular Genetics, City of Hope National Medical Center, Duarte, CA, USA.
Sun
Guihua
G
Yan
Jin
J
Noltner
Katie
K
Li
Wenyan
W
Buzin
Carolyn H
CH
Longmate
Jeff
J
Heston
Leonard L
LL
Rossi
John
J
Sommer
Steve S
SS
D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D040181:Genetic Diseases, X-Linked; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D010957:Plasmids; D012559:Schizophrenia / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
D035683:MicroRNAs