Copy Number Variations in Neuropsychiatric Disorders: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Judit Bene.

Neuropsychiatric disorders are complex conditions that represent a significant global health burden with complex and multifactorial etiologies. Technological advances in recent years have improved understanding of the genetic architecture of the major neuropsychiatric disorders and the genetic loci involved. Previous studies mainly investigated genome-wide significant SNPssingle nucleotide polymorphisms (SNPs) to elucidate the cross-disorder and disorder-specific genetic basis of neuropsychiatric disorders. Although copy number variations represent a major source of genetic variations, they are known risk factors in developing a variety of human disorders, including certain neuropsychiatric diseases.

  • psychiatric disorder
  • schizophrenia
  • bipolar disorder
  • major depressive disorder

1. Copy NVs umber Variations (CNVs) in Schizophrenia

Schizophrenia is a complex, clinically heterogeneous mental disorder with a prevalence of approximately 1% and a shorter life expectancy than the general population [31,32][1][2]. It is primarily characterized by disordered thinking, delusions, emotional deficits, and hallucinations. The onset generally occurs during late adolescence or early adulthood; although, rare cases have been presented with onset during childhood [32][2]. The aetiology of schizophrenia is thought to be multifactorial, based on complex interactions between genetic and environmental factors that influence early brain development and the trajectory of biological adaptation to life experiences [19,33][3][4]. Among the genetic variations described in patients with schizophrenia so far, CNVs are one of the most frequent genetic variations that might be causative [19][3].
The first reviews on the relationship between psychiatric disorders and chromosomal abnormalities were published in the early 1980s, including a study on chromosomal abnormalities associated with schizophrenia-like psychoses by Propping (1983) [34][5] and a study on fifteen X-linked and four autosomal abnormalities associated with psychoses by DeLisi and Lovett (1990) [35][6]. Previous research from family, twin, and adoption studies has shown strong evidence that genetic vulnerability underlies SCZ [36,37,38][7][8][9]. The first CNV associated with increased risk for schizophrenia/schizoaffective or bipolar disorder was the 22q11.2 deletion [39,40,41,42,43][10][11][12][13][14]. Individuals with the 22q11.2 deletions have a 20-fold increased risk of schizophrenia [44,45][15][16]. The deleted region contains genes that have been implicated in the aetiology of idiopathic psychosis [46,47][17][18]. According to Bassett et al., individuals carrying the 22q11 deletion have a highly variable phenotype and the average age at death is around their 40s [45][16]. Nearly 25% of carriers of the 22q11.2 microdeletion have schizophrenia-like symptoms [48][19]. In addition, reduced risk of SCZ has been associated with duplications of 22q11.2 [49][20].
The role of CNVs in the development of and/or contribution to schizophrenia is beginning to unfold [14,50,51][21][22][23] and it has been proposed that the CNV burden is higher in schizophrenia cases than in controls [50,52,53,54][22][24][25][26]. Remarkable differences in CNV burden have been observed between females and males in the general population and, also, in patients suffering from neurodevelopmental disorders, such as schizophrenia [55][27]. However, Han and colleagues demonstrated that variation in the gender CNV burden has no effect on known schizophrenia–CNV associations [29][28].
The genome-wide enrichment of rare duplications and deletions and the higher rates of de novo CNVs in SCZ cases compared to controls, as well as associated evidence, are shown to play a role in a number of specific loci, all contributing to the risk of SCZ development. According to a previous analysis of 15 schizophrenia-associated loci by Rees et al., higher rates were found in the case group compared to the control group in 13 of the 15 CNV-examined loci. Strong evidence has been demonstrated for the association between an increased risk of schizophrenia and 11 CNVs. The remaining four CNV loci represented weaker evidence and required further investigation [56][29]. The association with schizophrenia is now well established, accounting for approximately 1.0% of schizophrenia cases in the general population [11][30]. Former studies reported a higher de novo CNV mutation rate in SCZ in cases lacking a family history [57,58][31][32]. The results presented by Rees et al. demonstrated that circa 2.5% of individuals with SCZ carry at least one known pathogenic CNV [29,56][28][29].
Although most rare CNVs implicated in schizophrenia are unique and occur de novo, several were observed at recurrent genomic hotspots. This originates from the genomic architecture of hotspots, which are typically characterized by large repeated segments that increase the risk of replication errors and ultimately lead to the formation of CNVs [59][33]. Such genomic hotspots occur at the chromosome regions of 1q21.1, 3q29, 15q11.2, 15q13.3, 16p11.2, 16p12.1, 16p13.11, 17p12, and 22q11.2 and the neuropeptide receptor VIPR2. These loci have been associated with SCZ [59,60][33][34]. Although, further meta-analysis proved that the association between SCZ and VIPR2 is no longer supportive [56][29]. In a large, genome-wide study, Marshall et al. obtained definitive evidence of association for at least eight CNV loci in schizophrenia. Moreover, they found suggestive support for eight additional candidates for susceptibility and protective loci [11][30]. Based on previous findings, microduplications of 22q11.2 appear to confer protection from SCZ [49][20]. In other studies, strong statistical evidence has been proven for 12 risk CNVs associated with schizophrenia [13,51,61][23][35][36]. In a cohort of patients with schizophrenia, Hubbard et al. [68][37] investigated the cognitive ability between known schizophrenia-associated CNV carriers and noncarriers; they found that individuals harboring CNVs associated with SCZ exhibit significant cognitive impairment with clinical relevance. Furthermore, rare CNVs affecting gene sets (loss-of-function intolerant and synaptic gene sets) enriched for SCZ are specifically linked to poorer cognitive function in individuals with SCZ.
Previously, the majority of CNV analysis in schizophrenia has focused on disorder-specific CNV identification and only a few studies have investigated the effect of CNVs on specific sub-phenotypes of schizophrenia. In their study, Merikangas et al. aimed to explore the association between genome-wide CNVs and risk factors and subphenotypic features of SCZ beyond cognitive function. They examined the clinical outcome of CNVs that impacted differentially brain-expressed genes in a case-only analysis with 386 cases. Their results did not reveal any statistically significant association between CNVs impacting differentially brain-expressed genes and clinical severity, developmental delay, pre-morbid intelligence and intelligence quotient, and social cognition phenotypes. However, they found that advanced paternal age is associated with deletions in brain-expressed genes and brain-expressed CNVs are less common among those with a positive family history of psychiatric disorders. Based on their findings, the authors hypothesized that CNVs may represent one pathway to schizophrenia while a positive family history may indicate other genetic mechanisms that increase vulnerability to schizophrenia [52][24].
Larger (>500 kb) exonic CNVs have been shown in some research studies to have the highest burden in schizophrenia and they might have an effect on the phenotype in patients at risk of schizophrenia. Schizophrenia might be the only phenotypic feature of patients carrying CNVs; in other cases, schizophrenia is associated with intellectual disability or it develops as part of known genetic syndromes attributable to CNVs [19][3], such as 1q21.1 microduplication/microdeletion syndrome [70][38], Burnside–Butler syndrome (15q11.2 microdeletion) [71][39], or 22q11.2 microdeletion syndrome [44][15]. Based on previous studies, it appears that patients with schizophrenia who have an associated intellectual disability are more likely to carry pathogenic CNV [46,72,73][17][40][41]. Thygesen et al. found around a threefold higher frequency of pathogenic CNVs in individuals with psychosis and an intellectual disability than in the general schizophrenia population [72][40]. Moreover, Lowther and colleagues demonstrated how there is a significantly higher burden of pathogenic CNVs among patients with schizophrenia and a low IQ (IQ < 85) compared with those with an average IQ (IQ ≥ 85) [73][41]. These findings implicate that individuals with schizophrenia and a low IQ should be prioritized for clinical microarray testing in clinical and research contexts [31,72,73][1][40][41]. Derks et al. [74][42] found that in the case of very large CNVs (>1 Mb), the rates of CNVs were increased in cases with an ID and SCZ compared to ID-only cases. However, no significant differences were found in cases with CNVs smaller than 1 Mb. Based on their findings, the authors hypothesized that an ID plus SCZ is a severe form of SCZ, instead of a separate diagnostic category or a comorbid condition [74][42]. Rees and colleagues investigated the burden of 51 CNVs implicated in IDs for association with SCZ and 12 known schizophrenia-associated CNVs in a large case-control study. They found that a large proportion of the ID loci are likely to be risk factors for SCZ. Their findings indicate that a larger sample size will identify additional ID CNVs that are true SCZ risk factors. In addition, their results support the evidence for an aetiological overlap between neurodevelopmental disorders. A known ID-associated CNV occurring in a patient with SCZ should raise the suspicion that it is relevant to the psychiatric disorder in that individual [75][43].
Although SCZ commonly emerges during the late adolescence and early adulthood stages, in rare, severe cases, it might occur with onset during childhood. It is usually defined before the age of 13 years. Approximately 4% of patients encounter early-onset schizophrenia (EOS), which manifests either during childhood, before the age of 13, or during adolescence up to the age of 17 years [76][44]. It is suggested that a higher genetic load and increased symptom severity are observed in EOS. Familial investigations involving patients with childhood-onset SCZ (COS) reveal an increased rate of schizophrenic spectrum disorders pointing to familial transmission [77][45]. A previous study on patients with COS, adult-onset SCZ (AOS), and ancestry-matched controls presented that a higher percentage of patients with AOS (15%) exhibited novel structural variants compared to the controls (5%) [78][46]. In contrast, 28% of patients diagnosed with COS and 20% of patients with onset of SCZ before 18 years old carried one or more rare SVs [77][45]. In addition, another study provided evidence that 10% of individuals with COS demonstrated large chromosomal abnormalities at higher significant rates compared to patients with AOS [79][47]. COS patients also carried additional genomic lesions at 8q11.2, 10q22.3, 16p11.2, and 17q21.3, which have been previously connected with other disorders (e.g., autism, intellectual disability) [77][45]. Ahn et al. conducted whole genome genotyping, mainly focusing on 46 rare cases of CNVs, which have well-known risks for adult-onset SCZ. Compared to AOS, COS displayed a higher rate. Moreover, a higher rate was observed in cases of 22q11.2 deletion. Altogether, their observations provide support for the widely recognized pleiotropic impacts of these CNVs indicating shared abnormalities early in brain development.
Strong associations established between CNVs and psychiatric disorders are based on multicenter studies covering various populations. However, revealing the population-based prevalence and risk is crucial for determining the individuals’ CNV statuses in order to tailor precision health care. Sanchez et al. provided findings regarding the population-based prevalence and risk of psychiatric disorders associated with pathogenic CNVs in the Danish population. They examined six genomic loci (1q21.1, 15q11.2, 15q13.3, 16p11.2, 17p12, and 17q12) and, compared with previous studies, they found lower risk estimates of SCZ for most CNVs [62][48]. In another study of the Danish population, Olsen and colleagues found an elevated risk of 22q11.2 loci for SCZ; but, it was considerably lower than expected from previous studies [80][49]. Kushima et al. [81][50] performed a comparative CNV analysis on SCZ and ASD cases and found an increased genome-wide burden of rare exonic CNVs. They also identified 12 novel genes in the Japanese population that are potentially associated with SCZ/ASD. Kushima and colleagues in another study conducted an extensive, genome-wide CNV analysis within a predominantly Japanese population. Their investigation verified a significant correlation between X-chromosome aneuploidies with SCZ and 11 de novo CNVs [82][51]. Zhao et al. performed an investigation of the role of rare CNVs at 15q11.2 in SCZ in the Han Chinese population. A three-fold increase of deletions in cases over controls was found, which suggests an association between CNVs at 15q11.2 and SCZ in the Chinese Han population [83][52]. Furthermore, Saxena et al. analyzed the 15q11.2 loci on the Indian population and found no significant difference in the frequencies among the controls and patients; however, the sample size was limited [84][53].

2. CNVs in Bipolar Disorder

Bipolar disorder, previously known as manic depression, is a complex psychiatric condition with a high degree of phenotypic heterogeneity. It is characterized by recurrent episodes of depression alternating with periods of hypomania and/or mania, which affect thought, perception, emotion, and social behavior. The severity or magnitude of manic episodes can exhibit considerable variation and milder (hypo)manic episodes can occur in 2–3% of the general population [87][54]. BD can generally be divided into two subtypes: BD-I (characterized by episodes of mania and depression) and BD-II (hypomania and depression). BP is one of the leading causes of disability worldwide [88][55]. The observed lifetime prevalence of BD is approximately 2.4%, with an incidence of 0.6% for bipolar type I and 0.4% for bipolar type II [88][55]. The estimated heritability is around 60–85% [89][56]. The aetiology of BD is not well understood; however, due to intensive research over the last decade, more and more evidence has been revealed regarding the genetic background of the disorder, risk and vulnerability factors, and gene–environment interactions.
Although CNVs have been less well studied among the genetic factors in BD, certain CNVs have been reported to be associated with BD [90][57]. Zhang et al. investigated the frequency of singleton CNVs, which occur once in a dataset, among individuals with BD. These rarest CNVs are of interest since they are presumably enriched in de novo events. Singleton deletions over 100 kb in length throughout the genome were reported to be more frequent in BD cases compared to healthy controls; therefore, they are supposed to increase the risk of bipolar disorder [91][58]. The enrichment of de novo CNVs in individuals with BD was presented by Malhotra and colleagues as well [92][59]. In their trio-based study, 10 CNVs were identified as having a 5.4% rate in BD patients compared to a rate of 0.9% in the controls. In addition, Noor et al. found eight de novo CNVs, which were represented in a rate of 3.7% among BD individuals [93][60]. In a subsequent study, Georgieva et al. investigated the role of de novo CNVs in the aetiology of BD and compared them with de novo CNVs detected in SCZ. The presence of 15 de novo CNVs was revealed in BD, with a frequency of 4.1%. After combining their results with previous studies, they found that the increase in the de novo rate in BD over the controls was not significant. Compared to SCZ, the association between de novo CNV variants, especially large and rare CNVs, and BD seems to be more modest. In addition, de novo CNVs tend to be smaller in BD patients compared to SCZ [94][61].
Green et al. examined fifteen CNV loci previously known to be associated with SCZ and observed that three of them (16p11.2 and 1q21.1 duplications, 3q29 deletion) displayed significantly higher rates among BD patients compared to the control group. The 16p11.2 duplication showed the strongest evidence for association [64][62]. Their results confirmed that a significant difference is observed between BD and SCZ in terms of CNV occurrence, in particular, for large deletions exceeding 1 Mb in size. A pilot study by Chen and colleagues on the commonality and specificity of small common, and large CNVs in SCZ and BD demonstrated that the 10q11.21-22 variant, which affects the GPRIN2 gene involved in neurite outgrowth, is associated with an elevated risk of BD. In addition, variants in the 17q21.2, 9p21.3, and 9q21.13 regions displayed BD associations only. However, the 11p15.4, 15q13.2, and 22q11.21 variants are likely SCZ-specific, without BD associations [95][63].
The age at onset is often taken into account in CNV investigations. Some studies divided BD individuals into early- or late-onset subgroups, depending on the age of onset (AO) of the diagnosis [92,96][59][64]. Compared with healthy controls, in the patient cohort with an AO ≤ 18, the rate of de novo CNVs was significantly higher [92][59]; meanwhile, a higher frequency of microduplication CNVs and a significantly larger average size of singleton microdeletions were observed in patients with an AO ≤ 21 [96][64]. Two common CNV loci, microduplications on 6q27 and on 10q11, were enriched among early onset BD patients. The findings of Priebe et al. suggest that CNVs have an impact on the development of early-onset but not later-onset BD [96][64].
The identified CNVs in BD patients implicate a number of candidate genes involved in biological processes crucial to normal human development. The disruption of these gene functions is supposed to be involved in the pathogenesis of BD. The GRIK2 gene is located in the 6q16.3 CNV region, which is essential for brain development [97,98][65][66]. Noor et al. reported several CNVs that affect synaptic protein-encoding genes, such as DLG1, DLG2, DPP6, NRXN1, NRXN2, NRXN3, SHANK2, and EPHA5; neuronal splicing regulator genes, such as RBFOX1; and the CHL1 gene, which encodes a neuronal cell adhesion molecule.

3. CNVs in Major Depressive Disorder

Major depressive disorder is a mental health condition with a lifetime incidence of 10–20% [99][67]. It is characterized by a persistently low or depressed mood and a loss of interest in activities that used to bring pleasure. It can have a significant impact on individuals’ personal, social, and occupational functioning and affect quality of life. The morbidity from depressive perceptions and mortality from suicide attempts are substantial. Compared to several other psychiatric disorders, the heritability in MDD is lower, at around 37% [100][68]. The development of MDD is thought to be affected by a complex interaction of genetic, environmental, and neurobiological factors [101][69].
Based on initial research, no significant genome-wide CNV burden was observed in MDD [102][70]. Glessner et al. reported the first genome-wide association analysis of CNVs in MDD. The most significant locus was in the chromosomal region 5q35.1. Microduplications on 5q35.1 harbor the SLIT3, CCDC99, and DOCK2 genes, of which, SLIT3 is involved in axon development [100][68]. In their study, Degenhardt and colleagues found microdeletions in 7p21.3 and 18p11.32, microduplications in 15q26.3, and the combination of microdeletions/duplications in 16p11.2 to be more frequent in MDD patients compared with controls [103][71]. O’Dushlaine and colleagues investigated the association of rare CNVs with treatment-resistant MDD. They found that the contribution of rare CNVs to treatment-resistant depression appears to be modest [102][70]. A meta-analysis was carried out by Zhang et al. and demonstrated a notable increase in rare, short (<100 kb) deletions in MDD cases [101][69]. However, long, multigenic CNVs are potentially less likely to have significant effects on the risk of MDD. Based on these results only short deletions (10–100 kb) show a significant effect on MDD risk; however, the analysis of larger cohorts might provide more significant results about longer deletions [101][69]. As the observed deletions are particularly intergenic, it was hypothesized that their impact on MDD risk is due to the deletion of regulatory elements [101][69]. A higher prevalence of mood disorders has been observed in individuals with 15q13.3 duplications compared to individuals with reciprocal deletions (21.5% and 12%, respectively) [104][72]. According to Gillentine et al. [105][73], dosage changes in the CHRNA7 gene may be relevant to MDD and anxiety disorders. They observed a four-fold increase in the rate of CHRNA7 gain among individuals (adolescents, emerging adults) with MDD and anxiety disorders. A copy number polymorphism within the 10q11.21 region might be involved in the genetic etiology of suicide attempts in MDD, as Shitao Rao and colleagues suggested [106][74]. It potentially affects the expression of ZNF33B in the brain [106][74].
The role of CNVs in response to treatment with antidepressants was investigated in a study by Tansey et al. among individuals with MDD [107][75]. No significant association was observed between the antidepressant response and the presence of CNV, the overall number of CNVs, or the genomic CNV burden. However, a nominally significant association was seen with specific CNVs, such as exonic deletions of NRXN1 and duplications of 15q13.3. Notably, individuals harboring these CNVs exhibited a poorer response to antidepressant medications. A comparative study on the Danish population represented that the 1q21.1 deletion is associated with increased risk for MD and, exclusively in males, for BD [62][48].

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