Our study develops and applies a set of complementary methods for prediction of outcome variability in CNV carriers based on family data. By using these methods to model data from families with male probands carrying an extra Y chromosome, we (i) refine insights into the impact of XYY on several aspects of early cognitive and behavioral development, and (ii) show the general utility of family-based analyses for resolving interdependencies between outcomes in CNV carriers and cognitive-behavioral profiles in their first degree, non-carrier relatives. We address the implications of our results below and consider important steps for future work.
The correlation analyses in this study indicate that the degree of coherence between trait variability across CNV-carrying probands and their unaffected family members can vary greatly across traits. The strongest positive proband-family trait correlations were seen for FSIQ (0.63). Similar magnitudes of proband-family FSIQ correlations have also been reported in several other CNVs [22q11.2 deletion syndrome: 9, 16p11.2 deletion syndrome: 4, Down syndrome: 33, and Klinefelter syndrome 34]. This suggests that although most neuropsychiatric CNVs significantly impact FSIQ, many do so without disrupting the other sources of variance that underpin the well-documented familiarity of these traits in the general population 35. In other words, the causal pathways that mediate the negative impact of many CNVs on FSIQ must be distinct from those that explain intrafamilial FSIQ correlations. This principle does not seem to hold equally for vocabulary and matrix reasoning, however. In our present study of XYY syndrome, and in past studies of XXY and 16p11 deletion CNVs, the correlation between probands and first-degree relatives was stronger for verbal than non-verbal subcomponents of general cognitive ability 4,34.
Further, in contrast to the robustly positive proband-family correlations for FSIQ, we observe near-zero or negative proband-family correlations for several SRS-2 traits in XYY syndrome (0.088 > r > -0.26). This finding is surprising given that previous reports have found strong and positive proband-family intraclass correlation for social impairment in 16p11.2 deletion syndrome 4, and in the general population 36. One explanation for these findings is a differential rater effect across studies or syndromes. Another explanation is that the uncoupling of child from parent SRS-2 scores is driven in part by aspects of the underlying biology of XYY syndrome, such that carriage of an extra Y-chromosome introduces independent sources of variance in social functioning that disrupt the influence of familial factors. For example, psychopathology in XYY syndrome has been shown to affect the specificity of the SRS-2 screening form 3. The variability of the relationship between family and XYY probands across different traits, and the differences between findings in XYY and other CNVs, like 16p11 deletion syndrome, suggests that the utility of family data in predicting proband outcomes is likely to be both trait- and CNV-specific. Taken together, our findings suggest that knowing family scores for certain traits, such as FSIQ and vocabulary scores, is useful for predicting proband trait variation across CNV disorders, but that other traits, such as social impairment, can show highly variable proband-family correlations in different CNV disorders.
Our findings also emphasize the added value of modeling proband-family trait interrelationships within a regression framework 4,9,34. Specifically, by using regression to estimate proband offsets relative to family members versus the general population, we derived more refined estimates of the penetrance of XYY syndrome. For some traits, such as IQ and ADHD, our family-based models estimated offsets that differ from prior studies where trait scores in XYY syndrome were compared to those from recruited controls or standardized instrument distributions 31,37. We observed the largest offsets for ADHD-related traits, followed by ASD-related traits and FSIQ/vocabulary scores. In addition to allowing offset estimation, regression approaches also provide a quantitative framework for estimation of proband scores given known family scores. By analyzing these slopes, our study reveals that the average magnitude of FSIQ reduction in XYY probands relative to their first-degree relatives is expected to be the same (~ 1.3 Cohen’s d effect size) across different levels of proband and family IQ. This finding indicates that any potential ascertainment biases that might enrich for recruitment of families with unusually high or low FSIQs should not bias estimation of the penetrance of XYY for FSIQ reduction.
Regression analysis also provides a framework for multivariate modeling of proband outcomes from family data, which we harnessed to test for potential moderating effects of family FSIQ and perinatal variables on other proband-family trait interrelationships. These analyses revealed that there is a negative association between family IQ and proband SRS-2 scores: a higher family IQ score provides a protective effect for some aspects of social responsiveness. This finding demonstrates the need to examine cross-measure, family-to-proband relationships to better predict proband outcomes in the future. Multiple linear regression models also suggested that variability in XYY proband outcomes is not significantly related to variability in familial SES and perinatal variables. Thus, further expansion of such multiple linear regression methods could not only maximize our capacity to predict variation in proband outcomes, but also help to screen for potential moderators of proband outcome that could be modified for preventative or therapeutic benefit.
Finally, our framework implements a clustering method that can resolve the effect of an additional Y-chromosome on coherence within and between family members across several cognitive and behavioral measures. We observe co-clustering of traits into 4 broad groups (i) Family IQ and Proband ADHD-traits, (ii) Parent Psychopathology and Sibling ADHD-traits, (iii) Sibling Psychopathology, and (iv) Proband Psychopathology. All of the SRS-2 measures for a given family member cluster together, which is expected due to the high internal consistency of the SRS-2 38. The clustering of ADHD-traits in parents and unaffected siblings was also found in previous reports of children with ADHD 39. Notably, proband ADHD-traits clustered with family IQ measures, suggesting that the sources of ADHD-trait variation may differ between unaffected siblings and the XYY probands. While overall clustering patterns suggest a greater coherence between parent and sibling psychopathology compared to parent and proband psychopathology, all of the family IQ measures cluster together, suggesting that carriage of an extra Y-chromosome may disrupt coherence between probands and family members for psychopathology, but not for IQ measures. We anticipate that analysis of cross-trait, cross-relative correlation matrices will offer a parsimonious means of distilling large family-based behavioral datasets.
Our findings should be considered in light of several limitations and caveats. First, because the families in our cohort were not identified through a population-based sampling frame, they may not be fully representative of the full range of outcomes and background factors seen in XYY-probands and their first-degree relatives. Second, our study is cross-sectional in design and therefore cannot resolve potentially age-varying proband-family interrelationships. Third, observed correlations between rating scale scores can be influenced by methodological aspects which our study design does not directly model, such as parent versus child 40, or mother versus father 41 rater effects. Relatedly, our study design is not able to disambiguate the many potential sources of observed correlations between parent and child traits, which could include highly contrasting mechanisms - i.e., shared genetic determinants of IQ variation between probands and parents versus high parental psychopathology being driven by high caregiver strain, which in turn relates to proband psychopathology.