Byline: Nan. Lyu, Li-Li. Guan,
Hong. Ma, Xi-Jin. Wang, Bao-Ming. Wu, Fan-Hong. Shang, Dan. Wang, Hong. Wen,
Xin. Yu
Background
Schizophrenia (SCZ) is a severe,
debilitating, and complex psychiatric disorder with multiple causative factors.
An increasing number of studies have determined that rare variations play an
important role in its etiology. A somatic mutation is a rare form of genetic
variation that occurs at an early stage of embryonic development and is thought
to contribute substantially to the development of SCZ. The aim of the study was
to explore the novel pathogenic somatic single nucleotide variations (SNVs) and
somatic insertions and deletions (indels) of SCZ. Methods: One Chinese family
with a monozygotic (MZ) twin pair discordant for SCZ was included. Whole exome
sequencing was performed in the co-twin and their parents. Rigorous filtering
processes were conducted to prioritize pathogenic somatic variations, and all
identified SNVs and indels were further confirmed by Sanger sequencing.
Results: One somatic SNV and two somatic indels were identified after rigorous
selection processes. However, none was validated by Sanger sequencing.
Conclusions: This study is not alone in the failure to identify pathogenic
somatic variations in MZ twins, suggesting that exonic somatic variations are
extremely rare. Further efforts are warranted to explore the potential genetic
mechanism of SCZ.
Introduction
Schizophrenia (SCZ) is a severe,
debilitating, and complex psychiatric disorder that contributes substantially
to the global disease burden. As a multifactorial disease, a variety of genetic
and environmental factors play roles in the etiology. Genome-wide association
studies have identified a number of common risk loci, but all common polygenic
variations combined account for only 32-36% of the genetic risk for SCZ.
[sup][1] It is thought that the so-called "missing heritability" can
in part be explained by rare variations of large effect size. [sup][2] Next
generation sequencing technology enables the identification of novel rare
susceptibility loci at the whole genome and exome levels. In recent years,
researchers have characterized a polygenic burden arising primarily from rare,
disruptive mutations distributed across many genes enriched in discrete
biological processes [sup][3],[4],[5] such as synaptic network function.
Discordant monozygotic (MZ) twins
provide a unique window into the genetic factors underlying the disease
phenotype. Several studies have shown that phenotypic discordance between MZ
twins can be attributed to rare sequences differences caused by de novo events
such as chromosomal mosaicism (e.g., the discordant karyotypes mos 47, XX,
+21/46, XX and 46, XX), [sup][6] differing copy number variations (CNVs)
[sup][7],[8] and distinct single nucleotides. [sup][9] The genetic differences
between MZ twins can be regarded as an extreme form of somatic mosaicism
[sup][10],[11] resulting from postzygotic mutations that occurred at an early
stage of embryonic development and grew into two populations of cells with
genotypes different from that of the single fertilized egg. [sup][10] The
genetic comparison of discordant MZ twins represents a promising paradigm for
identifying rare novel candidates that may help to account for some or all
missing heritability.
Discordant MZ twin pairs have
been used previously to investigate the potential mechanism of SCZ. Many
studies have focused on differences in DNA methylation between discordant MZ
twins, [sup][9],[12],[13],[14],[15],[16] and series of genes have been
identified to play a role in gene networks relevant in the context of SCZ.
However, individual differences in DNA methylation are correlated with DNA
sequence variations. [sup][17] The genes that affected by differential
methylation between discordant twins also harbor various types of discordant
sequence variations that should not be overlooked. [sup][9] CNVs, a predominant
form of DNA structural variation, have been the subject of recent focus. Maiti
et al . [sup][18] observed somatic deletions (14q32.11, 8q11.21) and
duplication (19q13.41) in SCZ-affected twins, and Castellani et al . [sup][19]
observed an additional novel somatic deletion (7q11.21). Nevertheless, some
studies have failed to confirm somatic CNVs in discordant twin pairs,
[sup][20],[21] suggesting that there may be other underlying genetic causes of
the SCZ discordant phenotype including single nucleotide variations (SNVs) and
short insertions and deletions (indels), which are undetectable by the arrays
used to detect CNVs.
In a recent study, Castellani et
al . [sup][9] performed whole genome sequencing together with genome-wide
methylation analysis without the validation step of Sanger sequencing in two
families with MZ twins discordant for SCZ. A total of 71 genes harboring
somatic SNVs and indels were identified in affected twins. Nine missense
mutations were observed in exonic regions. Exonic regions containing about 85%
of known disease-related variants [sup][22] are valuable to be explored. To the
best of our knowledge, the aforementioned study is the only one to examine
differences in somatic SNV and indel profiles in MZ twins discordant for SCZ.
Evidence from further studies is needed. Therefore, we conducted high depth
exome sequencing of a family with an MZ twin pair discordant for SCZ to explore
possible relevant somatic mutations.
Methods
Ethical statement
This study was approved by the
Ethics Committee of the Institute of Mental Health, the Sixth Hospital, Peking
University. All subjects understood the purpose and procedure of the study and
provided informed written consents prior to enrollment.
Subjects
We sequenced the exomes of one
family with a pair of twins discordant for SCZ [Figure 1] from the Sichuan
Province of China. We included the elder sister of the twins in the study to
get more genetic information. All family members were of Chinese Han descent.
The demographic and clinical data of the family are shown in [Table 1]. The MZ
twins were 25-year-old males exhibiting highly similar physical
characteristics, including height, weight, pupil color, hair color, and hair
texture, and could not be easily distinguished by individuals other than their
parents. Twin 1 was healthy and without mental health problems. Twin 2 had been
diagnosed with SCZ and major depressive disorder. He had experienced delusions
of reference and persecution, auditory hallucinations, and thought broadcasting
since the age of 19 years. Then, these symptoms gradually lessened with regular
medication. He began to feel depressed at the age of 24 years, characterized by
diminished interest in his usual activities, a lack of energy, poor
concentration, and insomnia. The depressive symptoms lasted for 6 months and
then remitted. The parents and the elder sister of the twins were all
unaffected. There was no family history or personal history of severe
psychiatric or neurological illness.{Figure 1}{Table 1}
Diagnosis and assessment
All family members completed the
Structured Clinical Interview from the Diagnostic and Statistical Manual-IV-TR
Axis I Disorders-Patient. [sup][23] Diagnoses were made by an experienced
psychiatrist according to Diagnostic and Statistical Manual of Mental
Disorders, 4 [sup]th Edition, Text Revision criteria; and were confirmed by one
senior psychiatrist.
We used three scales, including
the Positive and Negative Syndrome Scale, [sup][24] the Scale for the
Assessment of Positive Symptoms, [sup][25] and the Scale for the Assessment of
Negative Symptoms [sup][26] to rate symptom severity. Overall individual and
social functioning were assessed by the Personal and Social Performance scale
[sup][27] and the Global Assessment of Functioning. [sup][28],[29]
The Wechsler Intelligence Scale
for Adult-Chinese Revised [sup][30] was used to estimate intelligence quotient.
A standardized questionnaire was designed to collect demographic data and
detailed information regarding the childhood environment, developmental
history, and family history of the individuals.
Genomic DNA extraction and exome
capture
Genomic DNA was extracted from
leukocytes obtained from peripheral blood using standard methods. Whole exome
sequencing was performed for four members of the family (I-1, I-2, II-2, and II-3).
Targeted enrichment was conducted using the NimbleGen SeqCap EZ Exome +
Untranslated Regions (UTR) Library (Roche NimbleGen, Madison, WI, USA), and
exon-enriched DNA was sequenced on the Illumina HiSeq2500 sequencing platform
(Illumina, San Diego, USA) according to the manufacturer's instructions to
obtain 125 bp paired-end reads.
Read mapping and variant calling
FASTQ files (i.e., the raw data)
were filtered to remove low-quality reads, and the remaining high-quality reads
were mapped onto a human reference genome (hg19) using the Burrows-Wheeler
Aligner version 0.6.2 (http://sourceforge.net/projets/bio-bwa/). Variants such
as SNVs and indels were called using a pipeline according to the Genome
Analysis Toolkit version 3.1 software (https://www.broadinstitute.org/gatk/).
Parameters of VariantFiltration for SNVs were set as follows: QD <2.0, MQ
<40.0, FS >60.0, HaplotypeScore >13.0, MQRankSum < −12.5,
and ReadPosRankSum < −8.0. Those for indels were set as follows:
QD <2.0, FS >200.0, and ReadPosRankSum < −20.0.
Variant annotation and
prioritization
ANNOVAR software
(http://annovar.openbioinformatics.org/en/latest/) [sup][31] was used to
annotate the variants. Sorting intolerant from tolerant (SIFT)
(http://sift.jcvi.org/) and polymorphism phenotyping 2 (PolyPhen2)
(http://genetics.bwh.harvard.edu/pph 2/) were used to assess the pathogenicity
of protein-altering variants. Evolutionary conservation was evaluated using
genomic evolutionary rate profiling (GERP++)
(http://mendel.stanford.edu/SidowLab/downloads/gerp/).
Several rigorous filtering steps
were performed to prioritize SNVs and indels: (1) variants that were present in
the affected twin and that were unshared by the healthy twin and the parents
were included; (2) the variants exhibited more than 20 x coverage; (3) variants
for which the percentage of reads supporting the newly identified allele
(defined as mutation frequency) was >20%, with at least three reads
supporting the mutation, were chosen; [sup][5] (4) variants in splicing regions
and protein-coding regions, such as missense, frameshift, stop-loss and
stop-gain mutations were included; (5) reserve variants with a minor allele
frequency ≤1% in a public database such as dbSNP 138, 1000 Genomes
Project Phase 3 (released May 2013), the National Heart, Lung, and Blood
Institute Exome Sequencing Project (ESP 6500), or the Complete Genomics CG46
database were chosen; (6) select variants were predicted to be damaging if they
had a SIFT [sup][32] score <0.05 and a PolyPhen2 [sup][33] score >0.85;
and (7) conservative variants (GERP++ [sup][34] score >2.0) were selected.
Variant validation
Sanger sequencing was performed
on an ABI 3730XL Genetic Analyzer (PE Applied Biosystems, Forest City, CA, USA)
for four members of the family (I-1, I-2, II-2, and II-3) to validate the
variants prioritized by the filtering steps. Forward and reverse primer
sequences for the candidate loci are listed in [Table 2].{Table 2}
Results
A quality summary for whole exome
sequencing is provided in [Table 3]. An average of 96.9% of the target regions
(96.5 Mb) were captured in each exome, and the mean depth of the target region
was 136x. In addition, 94.9% of the captured target exons were covered by ten
or more reads. A total of 580,849 variants (511,951 SNVs and 68,898 indels)
were called in the family, of which 84,545 variants (83,131 SNVs and 1414
indels) were in exonic regions and 18 variants (14 SNVs and 4 indels) were in
splicing regions.{Table 3}
There were 127,762 and 127,186
SNVs present in each twin, respectively, and 124,185 (97.4%) of the SNVs were
shared between the twins, supporting their monozygosity. Twin 1 and twin 2
shared 79.7% of the total SNPs with their father and 80.0% with their mother,
providing proof of the biological relationship of the family.
Three candidate somatic
variations passed our rigorous filtering steps [Figure 2], including 1 SNV in
CEP57 , 1 deletion in CTAGE5 , and 1 insertion in ORC2 [Table 2].
Unfortunately, none of the variants was confirmed by Sanger DNA sequence
analysis, as shown in [Figure 3].{Figure 2}{Figure 3}
Discussion
This study pioneers the
application of a family with MZ twins discordant for SCZ to explore pathogenic
SNVs and indels using whole exome sequencing. Sanger sequencing was performed
in our study to confirm all candidates. One somatic SNV and 2 somatic indels
with the potential to be pathogenic in the affected twin were identified.
However, none of these variations was validated via Sanger sequencing.
Although one previously reported
study has been successful in the identification of somatic variations in MZ
twins discordant for SCZ using high-throughput sequencing, [sup][9] we are not
alone in the failure to identify convincing somatic mutations that could be
responsible for the discordant phenotypes between MZ twins. Many studies using
a similar design have likewise failed. For instance, whole genome or exome
sequencing studies in MZ twins discordant for Crohn's disease, [sup][35]
multiple sclerosis, [sup][36] amyotrophic lateral sclerosis, [sup][37]
congenital heart defect, [sup][38] and congenital hypothyroidism [sup][39] have
failed to identify significant variants. These negative results support the
notion that somatic variants between MZ twins are extremely rare.
The rate of early postzygotic
mutation is exceptionally low. [sup][40] In a recent study, only 1 and 8
somatic SNVs were identified in two pairs of healthy MZ twins, respectively, at
the whole genomic level, and none was located in coding regions. The rate of
early postzygotic SNVs is estimated to be 0.04 x 10[sup]−9 and 0.34 x
10[sup]−9 per generation per position [sup][40] among two twin pairs,
which equates to one-thirtieth and one-third of the gremlin mutation rate.
Thus, the occurrence of somatic de novo mutation is so rare that it is not
easily observed, especially in exonic regions, which account for only 1-2% of
the genome.
Given that definitive differences
of SNVs and indels to explain the SCZ discordance were absent in our twin pair,
other possibilities should be considered. First, rare and large de novo CNVs
have emerged as an important genomic factor in psychiatric disease and occur
eight times more frequently in patients with sporadic SCZ; [sup][41],[42] we
could not exclude the possibility that the co-twins carry different CNV
profiles. Epigenetic differences could also explain the discordance in our twin
pair. Methylation differences between identical twins have been demonstrated as
early as the newborn stage [sup][43] and accumulate with age, [sup][44]
possibly resulting in phenotypic differences. Integration DNA sequencing and
other technologies, such as CNV and epigenetic analysis, to explore the
potential mechanisms of SCZ should be considered. Third, the tissue-specific
somatic variation could explain discordance. Somatic variations affect various
cell types and tissues depending on the time at which the mutation occurs.
[sup][45] In our twin pair, we did not detect somatic variations in leukocytes,
but this does not mean that other tissues, such as the central nervous system
(CNS) and other tissues originating from the ectodermal layer, do not harbor
pathogenic somatic mutations. Thus, the detection of brain tissue or hair
follicle (which is of ectodermal origin) should be considered in the future.
Experimental limitations should
also be considered. Whole exome sequencing primarily detects protein coding
regions and a small fraction of sequences adjacent to coding exons. Thus, most
noncoding regions, such as intergenic, intronic, and 3'- or 5'- UTR, are not
covered. It is possible that genetic differences might exist in regions outside
the assessable coding sequences.
In conclusion, we did not identify
convincing pathogenic SNVs and indels in coding regions by whole exome
sequencing in the family with MZ twins discordant for SCZ. This finding
suggests that the pathogenic genetic difference between MZ twins is too rare to
be detected. Further efforts are needed to investigate the potential mechanisms
of SCZ, such as noncoding DNA, CNS-specific somatic variations, and different
profiles of CNVs and epigenetics.
Financial support and sponsorship
This work was supported by a
grant from the National Natural Science Foundation of China (No. 81201039).
Conflicts of interest
There are no conflicts of
interest.
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