Schizophrenia typically presents in early adulthood or late adolescence. Men have an earlier age of onset than women, and also tend to experience a more serious form of the illness with more negative symptoms, poorer chances of a full recovery, and a generally worse outcome 
. Systematic reviews indicate that schizophrenia seems more common in men than in women (risk ratio of above 1.4
MicroRNAs (miRNAs) are a large family of small, non-coding RNAs that negatively regulate gene expression at the post-transcriptional level 
. In animals, miRNAs bind to complementary sites in target mRNAs, generally at 3′ untranslated regions (UTRs), to create imperfectly paired miRNA/mRNA heteroduplexes that inhibit translation or increase degradation of target mRNAs.
MiRNA genes are scattered among all the chromosomes in humans, except for the Y- chromosome. Most miRNAs are Pol II transcripts with a 5′ Cap and 3′ Poly(A) tail termed primary miRNA (pri-miRNA) 
. The pri-miRNAs are processed to hair-pin like structures termed precursor miRNA (pre-miRNA). The terminal loop of the pre-miRNAs are cleaved to generate miRNA/miRNA* partial duplex structures. One of the strands is then preferentially loaded in miRNA induced silence complex (RISC). Mature miRNAs often target 3′UTRs and reduce protein expression. Translational suppression and mRNA degradation, modes by which mammalian miRNAs regulate gene expression, do not require complete complementarity between the miRNA and target. Watson-Crick base pairing between seven consecutive nucleotides in the target mRNA's and nucleotides 2–8 (the “seed sequence”) at the miRNA's 5′ end is generally sufficient. For the majority of miRNA/target combinations, the seed sequence complementarity is a pre-requisite, although there are some exceptions which complicate target site predictions. For most miRNA/target combinations, a single nucleotide change in the seed sequence or a mutation in the miRNA or precursor affecting the Drosha/DGCR8 or Dicer/TRBP processing step can result in altered function or creation of a novel miRNA 
It is estimated that approximately one-third of human protein coding genes are post-transcriptionally controlled by miRNAs (reviewed in 
). Many microRNAs are conserved in sequence and function between distantly related organisms 
miRNAs regulate various biological functions including developmental timing, cell proliferation, neuronal cell fate, apoptosis (reviewed in 
), neuronal gene expression 
, brain morphogenesis 
, muscle differentiation 
, and stem cell division 
. It is speculated that condition-specific, time-specific, and individual-specific levels of gene expression may be due to the interactions of different miRNAs accounting for more accurate genetic expression of various traits 
. The large number of miRNA genes, the diverse expression patterns and the abundance of potential miRNA targets suggest that miRNAs may be a significant but unrecognized source of human genetic disease, including neuropsychiatric disorders. A sequence variant in the binding site for the miRNA miR-189 in the SLITRK1 (MIM # 609678) mRNA has been shown to be associated with Tourette syndrome 
. However, two recent studies of ~800 and ~2300 Tourette syndrome patients and family members found non-transmission of the variant in two families in each study from parent to affected child 
the former study suggested that the variant may be a rare Ashkenazi Jewish population variant. In addition, components required for miRNA processing and/or function have also been implicated in fragile X mental retardation 
, chromosome 22q11 deletion syndrome (DiGeorge syndrome) 
and cancer 
, pointing to the wide ranging involvement of miRNAs in disease.
To explore the possibility that high risk structural variants in the microRNA genes could predispose to schizophrenia, we chose the X-chromosomal miRNA genes available at the time of the study. 59 microRNA genes on the X-chromosome were sequenced in 193 unrelated male patients with schizophrenia and 191 male controls. The one tested hypothesis is that ultra-rare variants in the X-linked microRNAs predispose to schizophrenia, consistent with reduced fertility in schizophrenia and consequent elimination of high risk X-linked mutations within a few generations 
. This analysis should be distinguished from linkage disequilibrium/Hap Map analyses in which thousands of hypotheses are typically being tested.