Following the Trail From Genotype to Phenotypes

Until recently, no one could imagine a genetics-first study of the size and depth described in this issue of JAMA Psychiatry by D’Angelo and colleagues.1 The more familiar phenotypefirst approach defines affected individuals based on DSM or other criteria and then looks for genetic risk variants. Based on this approach, rare genomic variants, including copynumbervariants (CNVs) suchas 16p11.2duplications and deletions, havebeen identifiedas significant risk factors in autism spectrum disorder (ASD), intellectual disability, and schizophrenia, albeit each variant in a small fraction of individuals.2 Because thesephenotypes are individually rare, trying tounderstand them in associationwith a genomic variant within the clinically defined (phenotype-first) population used to define its contribution to risk is impractical.3 Just as gene finding has required the formation of ever larger supergroups of investigators to accrue enough sample size, D’Angelo and colleagues1 represent a consortiumof consortia, including the Cardiff University Experiences of ChildrenWithCopyNumberVariants (ECHO)study, the 16p11.2European Consortium, and the Simons Variation in Individuals Project (VIP) Consortium. They contrast this populationwith relatives who do not have this CNV and with an antiparallel populationwith this same16p11.2 regiondeleted.Thismethod allows the investigators to understand the degree to which these reciprocal genomic events contribute to the disorders withwhich theywere initially identified—ASDandschizophrenia—and to examine brain function more broadly. Inparticular, theSimonsVIPstudybeganasa search tounderstand one possible cause of ASD.4 The final results, which pool datawithmultiple other samples, indicatemuchbroader cognitive and behavioral deficits than ASD and additional effects on co-occurring medical conditions. As this report and othersmake clear, 16p11.2 CNVs are one of themost common findingsassociatedwithASD,butmostchildrenandadultswith these genomic variants do not have ASD.1 One of themost remarkable features of the report is its serious attempt to integrate findings across different areas of assessment.This feat isnot evenattempted inmany reports. The reader not only learns that distributions of IQ in deletions and duplications are shifted downward from intrafamilial control individuals but can follow the associations betweendecreases in IQ and other features, from ASD to seizures to gross motor delays tobodymass index (BMI) tohead circumference.As geneticistsbecomemorefamiliarwithpsychometricdata, theneed to consider cognitive defects when measuring many behavioral domains and neurologic risk is increasingly being recognized. If a child or an adult is less able to reason and remember, theprobabilityofdeficits insocialcommunicationskillsand increases in psychopathologic features are well known.5 This findingmay be reflected in the observation that 16p11.2 duplication probandswith ASD have IQs of nearly 2 SDs lower than thosewith theduplicationwhodonothaveASD; this isnot the case in thosewith the deletion. In contrast, although BMIwas overalldecreased intheduplicationgroup, thedecreasewasnot related to an ASD diagnosis, IQ, or epilepsy. The stronger relationship between CNVs and IQ than betweenCNVsandsocialdeficits, languagedelay,orotherASDfeatures is inconvenient for those of us whowish to have simple measuresofneatly separatedpsychological dimensions, as exemplified in theResearchDomainCriteria (https://www.nimh .nih.gov/research-priorities/rdoc/index.shtml). At least in this population,cognitiveandsocialcommunicationdeficitsemerge fromasingle riskvariant6coupledwithunknowngeneticorenvironmentalmodifiers. Insteadof asserting aunique relationship with a DSM-defined disorder, this report is an excellent example of “biting the bullet” of a less dramatic finding (eg, shifts downward in cognitive function) than finding a causeof ASD—butonethatmayilluminateabroadunderstandingofneurobiological dysfunction acrossmultiple symptom domains. In addition to calling into question the separation between symptomdomains, the IQdata also highlight a longstanding challenge todevelop continuousmeasures of behavior functioning.7 Dramatic variation in the IQs of the children andadultswith 16p11.2duplicationshasbeen found.The shift downward fromunaffected relatives is consistent, but thedegree of shift and the absolute scores are not. The IQ range of unaffected familymembers extended towell above 100. If no continuous measure of intelligence included above-average functioning as well as severe disability, identifying a relative decrease would not be possible. Unfortunately, although we havemeasuresof severityofASDfeatures,wedonothavewellvalidated, continuous measures that range from superior social behavior or above-average emotional regulation to deficits in these areas. In addition to the general downward skewing of IQ in the duplication and deletion groups, the report also describes intriguingdifferences in the tail endsof the IQdistribution,with proportionally more children with 16p11.2 duplications having severe intellectual disabilities as well as more having average intelligence than those with deletions. Although this greatervariationmaypoint topossible relationshipswithother genetic variants, it may also reflect the substantial challenge of ascertainment in genetics-first studies. The reality is that chromosomalmicroarrays areonlyperformed for a clinical (or clinical research) indication. Identified probands are therefore likely to have more severe neurodevelopmental impairRelated article page 20 Opinion