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these populations relative to white British persons [130] . The data suggests a genetic component as the risk of
SCZ increases with the relatedness of an individual to persons affected by SCZ. The risk of developing SCZ
increases the most for individuals with affected members of their immediate family, from 6%-13%. Other
possible explanations include a predisposition for migration in schizophrenic individuals, misdiagnosis,
drug use, and various socioeconomic factors. In a retrospective cohort study, investigators examined racial/
ethnic disparities in SCZ diagnoses. The authors examined three classes of factors related to SCZ diagnoses,
predisposing factors, demographic measures like age and ethnicity; enabling factors, such as insurance status
and socioeconomic measures; and need factors, such as symptoms and substance use. The investigators
found that the predisposing factors of male gender, Hispanic ethnicity, and African American race increased
the likelihood of SCZ diagnosis [131] . A study with found that while polygenic risk scores were efficacious in
distinguishing schizophrenic patients from healthy controls of European ancestry, that polygenic risk scores
were less efficacious with African American participants [132] .

Detection of transcriptional signatures of SCZ provides new insight into the genetics basis of the diseases.
To study the role of the microbiome in the etiology of SCZ, Olde Loohuis et al. [133] , collected the blood
of 192 participants including patients with SCZ and BD and performed RNAseq to determine which
microbes were present. Patients diagnosed with SCZ were found to have a more diverse microbiome than
the other participant groups. After comparing SCZ cases to controls, the investigators determined that this
was due to an overall increase in the microbial burden among SCZ patients [133] . A transcriptional analysis
of lymphoblastoid cell lines from 268 cases and 446 controls showed 1,058 genes that were differentially
expressed between SCZ cases and healthy controls [134] . A further analysis of the gene expression data found
that SCZ cases demonstrated upregulation of genes related to immunological function and downregulation
of genes related to apoptosis or non-immune functions [134] . Schizophrenics were also demonstrated to have
a greater number of copies of the ribosomal RNA gene than healthy controls [135] . Brennand et al. [136] used
human induced pluripotent stem cells (hIPSC) derived neurons to model the neurobiology underlying
SCZ. They found reduced arborization and synaptic contacts in the hIPSC neurons of SCZ patients, though
spontaneous neuronal activity was found to be normal. They found 596 genes that were differentially
expressed between the hIPSC neurons of SCZ patients and those of healthy controls. Treatment of hIPSC
neurons with loxapine, an antipsychotic, increased the number of synaptic contacts and the expression of
receptors crucial in glutamatergic signaling [136] .

CONClUsION
SCZ is a serious mental disorder affecting millions of people worldwide, but the underlying mechanisms
remain unknown. The common variants identified by the GWAS only explain a small fraction of the
estimated SCZ heritability. The development of NGS provides an unprecedented opportunity to identify the
SCZ candidate genes and variants and research their functions. The analysis of the rare variants is timely
and achievable in its aims of understanding the relationship between genotype and phenotype underlying
SCZ. Multiple bioinformatics tools have been developed to detect rare variant associations in case-control
and family studies. Targeted resequencing, WES and WGS have been used to identify the rare variants
associated with SCZ. Although there are numerous challenges in SCZ research, the rare variant studies can
provide useful information for characterizing the rare mutations and elucidating the genetic mechanisms by
which the variations cause the SCZ and other mental illnesses. It could help biomedical scientists develop
better diagnostic and treatments for individuals with psychiatric disorders.

DeClaRaTIONs
Acknowledgments
We thank supports from the Howard University Junior Faculty Writing & Creative Works Summer
Academy.