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De Francesco et al. J Transl Genet Genom 2024;8:102-18 https://dx.doi.org/10.20517/jtgg.2023.51 Page 104

initial methodological overview of research designs in quantitative behavioral genetics, the characteristics of
INT/EXT clusters and their contribution to the debate on categorical diagnostic systems versus dimensional
approaches will be examined. Additionally, behavioral genetic evidence supporting the need for a
dimensional approach to psychopathology will be presented. The review will then emphasize the
contribution of twin designs in differentiating between ADHD and CDS. Finally, available data on the
comorbidity between CDS and INT-EXT disorders will be reviewed, with a special focus on the results from
the first twin studies addressing this issue, potentially offering valuable insights for clinical monitoring at
both individual and familial levels.

Behavioral genetics: definition and historical overview
Behavioral genetics can be defined as a research field whose aim is to investigate how the interplay between
genetic and environmental factors can concur to explain individual differences in psychopathology,
[10]
temperament traits, and behavior .

Its roots can be traced back to the 1970s, when the hypothesis that behaviors and psychopathology could be
influenced not only by environmental factors, but also by genetics, was postulated. Since then, more
importance has been attributed to the genetic underpinnings of psychological traits and the concept of
“genetic predisposition” was gradually introduced . Therefore, during the 1980s, the contribution of the
[11]
environment was almost completely excluded from the research on the etiopathogenesis of
psychopathology, whereas the influence of genes on various phenotypes became its main focus . However,
[10]
when considered separately, neither genetics nor the environment was sufficient to explain the
etiopathogenesis of psychopathology, as they each accounted for only up to 50% of the variance; hence, a
more comprehensive perspective was needed. The roles of both “nature” and “nurture” started to be
considered equally important in understanding and explaining individual differences in complex behavioral
traits . As a result, the current literature agrees that the phenotypic variance of specific traits is shaped by
[10]
the constant interplay of genetic and environmental factors. For instance, exposure to given environments
can be driven by biologically determined elements, whereas being exposed to certain environments may
alter the genetic pathways through epigenetic changes . Consequently, behavioral genetics has gradually
[10]
started to adopt a bio-psycho-social approach, according to which psychopathology emerges from the
interaction between the individual’s biological features and the environment, which can represent
[12]
alternatively a risk or a protective factor for the development of psychiatric disorders . The growing
interest in this field of research has progressively led to the development of disciplines, such as epigenetics
and quantitative genetics, devoted to the implementation of increasingly effective methodologies for
studying the etiological factors underlying psychological phenotypes.

Quantitative genetics
The main goal of quantitative genetics is to assess the interplay of genetic and environmental factors in
shaping specific phenotypes. The overall genetic variance of a complex trait can be divided into three
components: (A) genetics, (C) shared environment, and (E) unique environment . Specifically, A denotes
[13]
the contributions deriving from additive genetic effects (i.e., the sum of the effects from all gene variants
influencing the trait independently). C stands for the shared environmental factors, encompassing
influences common to twins within a family, especially during childhood and adolescence (e.g., parental
behaviors, socioeconomic status of the family, the rearing environment, etc.) or shared in utero during the
gestation (e.g., exposure to the same maternal hormones). Meanwhile, E represents unique environmental
factors that account for influences specifically acting on an individual (infections, peer relationships,
lifestyle, etc), and also includes measurement error . The primary research designs employed to explore
[14]
genetic and environmental influences on phenotypes are adoption and twin studies . Adoption studies
[15]
evaluate the genetic and environmental contributions to the similarities among family members in complex