77

RANSLATIONS

T

2

Copy Number Variation: What Is It and WhatHas It Told Us About Child Psychiatric

Disorders?Anita Thapar, M.B.B.Ch., F.R.C.Psych., Ph.D., F.Med.Sci., ANDMiriam Cooper, M.B.Ch.B., M.R.C.Psych., B.Sc.

opy number variation is now recognizedas an important class of risk factor for

C several child psychiatric disorders. In this

article, we first explain what copy number vari-ants (CNVs) are. We then consider key findingsand what these have told us about the etiology ofthese conditions. Finally, we discuss whetherthese findings can yet translate into clinicalpractice.

WHAT ARE COPY NUMBER VARIANTS?There are multiple types of genetic alterationsthat contribute to human variability, many ofwhich have yet to be fully characterized orproperly understood. This genetic variation caninvolve differences in the DNA nucleotide se-quence as well as changes in chromosome struc-ture. Single nucleotide polymorphisms (SNPs) arecommon variants of individual nucleotide se-quence that are frequently observed in the pop-ulation (>1%). CNVs are a type of structuralvariant involving alterations in the number ofcopies of specific regions of DNA, which caneither be deleted or duplicated. These chromo-somal deletions and duplications involve fairlylarge stretches of DNA (that is, thousands ofnucleotides [>1 kb], which may span manydifferent genes) but can range considerably insize as well as prevalence. As is the case for othertypes of genetic mutations, some CNVs areinherited whereas others spontaneously arise denovo. To date, most CNV research in psychiatryhas focused on rare forms of copy number vari-ation that occur with a frequency of <1%.

WHAT ARE THE CNV FINDINGS FORCHILD PSYCHIATRIC DISORDERS?There are several well-characterized rare de-velopmental phenotypes caused by CNVs ofknown pathogenicity, such as Velocardiofacial,

JOURN

www.jaacap.org

Prader-Willi, and Smith-Magenis syndromes.Although the role of most CNVs is far lessclear, there is now growing evidence that thegenetic architecture of more common psychiat-ric and neurodevelopmental conditions includesdifferent types of both common and rare ge-netic variation.1 An increased burden of rareCNVs has been observed and replicated inseveral conditions. These include autism spec-trum disorder (ASD), attention-deficit/hyper-activity disorder (ADHD), and intellectualdisability (ID), as well as schizophrenia. CNVsalso contribute to risk of idiopathic epilepsy.

Risk factors for complex disorders tend to be ofsmall effect size (odds ratios of <2), and this hascertainly proved to be the case for individualSNPs. Conversely, the types of CNVs that havebeen found to be associated with neuro-developmental and psychiatric disorders havebeen of considerably greater effect size.2,3 This isnot surprising, because as the types of CNV mu-tations that have been studied are so rare, theireffects have to be large to be detected in modestsample sizes. In fact, so far large rare CNVs showthe strongest and most consistent associations,and size and burden of CNVs seem to be pro-portional to phenotypic severity. Large rare CNVsappear to be further enriched in individuals whohave ASD or ADHD with comorbid ID,3,4 andthe burden appears to be even greater in thosewith ID and congenital anomalies.2,3

Psychiatric disorders mainly have a complex,multifactorial etiology. Apart from some infre-quent exceptions (e.g., known genetic syndromes,fetal alcohol syndrome, congenital rubella), asingle risk, whether genetic or environmental, isneither necessary nor sufficient to result in dis-order. Thus, typical of all complex disease epi-demiology, many carriers of risk CNVs will notdisplay a psychiatric or neurodevelopmentalphenotype, and not all those affected will possess

AL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY

VOLUME 52 NUMBER 8 AUGUST 2013

TRANSLATIONS

the risk variant. As an analogy, although cigarettesmoking is a well-established risk factor of largeeffect size, not all smokers develop lung cancer,and not all individuals with lung cancer havesmoked. There are likely multiple types of risksand pathways that lead to the same child psy-chiatric disorder.

WHAT HAVE CNV FINDINGS TOLD US?CNV Mutations Can Arise De NovoGenetic data from parents are required to identifywhether variants are inherited or have arisen denovo. So far, although CNVs have been found tobe both inherited and de novo in origin, muchinterest has focused on de novo mutations. Suchmutations are associated with risk of ASD, ID,and schizophrenia but would not contribute tothe familial transmission of these disorders.Increased paternal age has been found to beassociated with some types of mutations, as wellas with risks of both ASD and schizophrenia.Rare de novo CNVs do not, however, necessarilyexplain all the observed paternal age effect.

CNVs Span Traditional Diagnostic BoundariesAlthough ASD, ADHD, schizophrenia, and IDhave clinically distinctive defining features, onekey and consistent finding is that the CNVsassociated with each of these disorders showsignificant overlap with each other.1,5 That is,the same CNV is associated with increased riskof different types of disorders: this is knownas pleiotropy. This phenomenon is most consis-tently observed for disorders considered tohave strong neurodevelopmental origins (ASD,ADHD, schizophrenia, and ID). This observationhighlights that the same genetic risks operateacross diagnostic categories. That is also true forother risk factors.

CNVs Can Provide Clues to BiologyThe chromosomal regions that harbor CNVsobserved to be associated with psychiatric disor-der are located at multiple genomic regions onmany different chromosomes, and each deletionor duplication often encompasses several genes.So, are these simply randomly distributed muta-tions, or are their locations significant? Multipletypes of evidence suggest that CNV locationsprovide meaningful clues to the neurobiology ofthese disorders. Genes code for proteins that areinvolved in different biological processes. The

JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATR

VOLUME 52 NUMBER 8 AUGUST 2013

functions of different genetic elements are notfully understood; however, genetic findings canbe used to make inferences about the biologicalprocesses involved. Although there are somemethodological limitations to this approach,consistent patterns of findings are emerging. Therare CNVs found to be associated with ASD,ADHD, schizophrenia, and ID all seem to spangenes that converge on meaningful biologicalprocesses. For example, CNV studies of ASD,schizophrenia, and ID have strongly implicateddisrupted synaptic function. Studies of ADHDhave suggested involvement of nicotinic acetyl-choline receptor pathways, glutamatergic trans-mission (also found in schizophrenia), and genesinvolved in neural development.

WHAT ARE THE CLINICALIMPLICATIONS—AND WHAT NEXT?To interpret CNV findings in a clinically mean-ingful way is challenging. Essentially it is difficultto prove causal pathogenic effects. Moreover,most child psychiatric disorders, including thosethat have been found to be associated with CNVs,are multifactorial in origin and not caused by asingle risk factor. In many cases, the presence of aspecific CNV will not necessarily imply that itplayed a role in causing disorder, and, for someCNVs, carriers can be unaffected. Inferring cau-sality is further complicated by the high levels ofcomorbidity between different child psychiatricand developmental disorders. Furthermore, in-complete penetrance, pleiotropic risk effects, andde novo mutations make estimating the risk ofdisorder recurrence particularly complex. Theetiological role of environmental factors and gene–environment interplay in complex disordersshould also not be overlooked—nor should thecontribution of other classes of genetic variant.

Advances in techniques for detecting submi-croscopic chromosomal abnormalities havemeant screening for rare CNVs in idiopathic IDhas become increasingly commonplace. Rare,syndromic forms of ASD and other psychiatricdisorders will likely require similar types ofassessment and counseling. However, for mostchildren who are under the care of child psychi-atrists, it seems unlikely that routine CNV test-ing will become established practice in the nearfuture for the majority of individuals unlessperhaps they also have ID or multiple develop-mental morbidities. Prevention and treatment

Y

www.jaacap.org 773

THAPAR AND COOPER

strategies based directly on genetics also remaindistant.

Nonetheless, the establishment of CNVs asrisks for psychiatric disorders is an importantbreakthrough. The findings highlight com-monalities across different neurodevelopmentaldisorders. The genes indexed by CNVs arebeginning to provide valuable biological insightsand clues to patterns of altered brain develop-ment and function that accompany disorderssuch as ASD, ADHD, and schizophrenia. CNVfindings, by shedding light on pathogenesis, cancontribute to progress in developing novel in-terventions and risk modification strategies thattarget relevant risk processes in the nearerfuture. &

JOURNAL

774 www.jaacap.org

Accepted May 23, 2013.

Drs. Thapar and Cooper are with the Institute of Psychological Medi-cine and Clinical Neurosciences and the Medical Research Council(MRC) Centre for Neuropsychiatric Genetics and Genomics at CardiffUniversity School of Medicine.

This research was supported by the MRC (UK) and the Wellcome Trust.

The authors thank Michael O’Donovan, F.R.C.Psych., Ph.D., of CardiffUniversity, for helpful comments and Rhys Bevan Jones, M.R.C.Psych.,of Cardiff University, for reading through the article.

Disclosure: Drs. Thapar and Cooper report no biomedical financialinterests or potential conflicts of interest.

Correspondence to Anita Thapar, M.B.B.Ch., F.R.C.Psych., Ph.D.,F.Med.Sci., Cardiff University, School of Medicine, Heath Park,Cardiff, CF14 4XN, UK; e-mail: thapar@cf.ac.uk

0890-8567/$36.00/ª2013 American Academy of Child andAdolescent Psychiatry

http://dx.doi.org/10.1016/j.jaac.2013.05.013

REFERENCES

1. Sullivan PF, Daly MJ, O’Donovan M. Genetic architectures of

psychiatric disorders: the emerging picture and its implications.Nat Rev Genet. 2012;13:537-551.

2. Cooper GM, Coe BP, Girirajan S, et al. A copy number variationmorbidity map of developmental delay. Nat Genet. 2011;43:838-846.

3. Girirajan S, Brkanac Z, Coe BP, et al. Relative burden of large CNVson a range of neurodevelopmental phenotypes. PLoS Genet. 2011;7:e1002334.

4. Williams NM, Zaharieva I, Martin A, et al. Rare chromo-somal deletions and duplications in attention-deficit hyper-activity disorder: a genome-wide analysis. Lancet. 2010;376:1401-1408.

5. Williams NM, Franke B, Mick E, et al. Genome-wide analysis ofcopy number variants in attention deficit hyperactivity disorder: therole of rare variants and duplications at 15q13.3. Am J Psychiatry.2012;169:195-204.

OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY

VOLUME 52 NUMBER 8 AUGUST 2013