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families. Approximately 40% of SCZ patients attempt suicide and are at eight-fold higher risk than the
general population.

The underlying biological mechanisms of SCZ remain elusive. The disease is known to be accompanied
by dysfunction in neurotransmission; morphological changes in prefrontal cortex, hippocampus, and
[6-9]
striatum; and alterations in the signaling between brain regions as well . Some environment factors such
[10]
as childhood trauma can increase the risk for SCZ . The twin and family studies suggest that the genetic
heritability is the most significant risk factor for developing the disease. For example, monozygotic twins
[11]
are more than twice as likely to be diagnosed with SCZ than dizygotic twins . Determining the genetics
of SCZ and complex disorders is further complicated by evolutionary genetic theory. Though it would seem
that common complex heritable disorders, should be phased out through natural selection, several plausible
theories have been used to explain this paradox, including balancing selection, heterozygote advantage,
[12]
pleiotrophy, and polygenic models . The polygenic model seems to be supported throughout the literature,
however determining the precise number of loci that contribute to a particular complex disorders or traits
[12]
has been challenging . Many genetic approaches have been applied to the investigation of genetic variants
[12]
that play an important role in the development of SCZ . Genome-wide association studies (GWAS) have
identified single nucleotide polymorphisms (SNPs) associated with increased susceptibility in SCZ [13,14] . The
loci revealed by GWAS have diverse biological roles including neurotransmission, inflammatory response,
[15]
glucose metabolism, and cell adhesion . Several studies have demonstrated weak associations between
common variants and major psychiatric disorders such as SCZ, bipolar disorder (BD) and major depressive
[16]
disorder (MDD) . However, most of the common variants have small or moderate effects on the disease
risk, and a large proportion of the heritability remains unexplained.

Rare variants, usually defined as alleles with a minor allele frequency (MAF) < 1% in population, have been
demonstrated to contribute to the missing heritability in SCZ. The use of next-generation sequencing (NGS)
technologies like targeted resequencing, whole exome sequencing (WES) and whole genome sequencing
(WGS) have allowed scientists to identify the rare variants and estimate the deleterious mutation load to
[17]
investigate the contribution of rare mutation to the complex diseases . In a SCZ study, WES for 2,536 cases
and 2,543 controls showed enrichment of rare disruptive variants in genes related to calcium channels and
[18]
the fragile X mental retardation protein . Identifying rare variants is important for prioritizing potential
pathogenic targets for diagnosis and drug discovery. This review will focus on the development of rare
variant association tools and recent discoveries for investigating rare variants implicated in SCZ using NGS.

COmmON VaRIaNTs Vs. RaRe VaRIaNTs
Common vs. rare variant hypotheses for complex diseases
There are two contemporary hypotheses concerning the genetic contribution of sequence variants for
[19]
common complex disorders such as cancer and SCZ . The “Common Disease, Common Variant” (CD-CV)
hypothesis argues that common diseases are associated with the common genetic variants. It means that a
few variants with high frequencies in the population are the major contributors for a common disease with
complex traits. However, the common variant can only account for a portion of heritability of many genetic
[20]
disorders . One investigation demonstrated that the association of common variants with many disorders
[21]
and complex traits only accounted for approximately 30% of the heritability in SCZ . This finding implies
that the missing heritability is due to undiscovered common variants and rare disruptive variants. To
address the missing heritability issue, the “Common Disease, Rare Variant” hypothesis suggests that multiple
rare variants with relatively high penetrance contribute to the genetic component of common diseases.
These genetic variations are usually found within less than one percent of the population. Some studies have
demonstrated that rare variants could account for a substantial percentage of the missing heritability in
[22]
complex diseases and phenotypes . Determining the precise sources of missing heritability is a necessary
hurdle to understand the etiology of neuropsychiatric disorders.