Early behavioral indices of inherited liability to autism

Abstract

Recent developmental studies have indicated that autism spectrum disorder (ASD) may arise from critical combinations of specific early neurobehavioral susceptibilities, each of which may be traceable to partially-independent sets of genetic variation. These susceptibilities and their respective genetic origins may not relate to the characterizing symptoms of ASD (after it develops) in a straightforward way. Furthermore, some of the contributory liabilities may not necessarily be specific to ASD, and may account for “missing heritability” in molecular genetic studies. Identifying common genetic variants linked to these underlying traits rather than to a diagnosis of ASD may account for a greater share of the population attributable risk for ASD, especially if autism represents a developmental consequence of earlier-interacting susceptibilities. To elucidate the early endophenotypic structure for the development of autism will require testing of a next generation of viable early phenotypic candidates in a manner that is epidemiologically rigorous, in which the distinction between ASD prediction in the general population and ASD prediction of autism recurrence (i.e. within families affected by ASD) is closely attended to, and in which the relationships between endophenotypic candidates are mapped and normed.

Brain function distinguishes female carriers and non-carriers of familial risk for autism

“…The possibility of a parsimonious effect of sex-and therefore a convergent neural signature of its effect in modulating phenotypic expression of inherited liability-arises from the observation that, along the autism spectrum and across its many genetic causes, the symptom structure of the condition is unitary in nature. Thus, disparate symptoms might arise from shared neural mechanisms [80,81] that are uniquely vulnerable to disruption early in life-less among females, more among males-in individuals who inherit ASD susceptibility [5,82,83]. In the present study, we failed to replicate an array of specific brain responses that were reported to differentiate siblings of ASD probands from unrelated controls in prior research.…”

On the Nature of Monozygotic Twin Concordance and Discordance for Autistic Trait Severity: A Quantitative Analysis

“…If our findings on the relative non-heritability of severity ratings among clinically-affected cases are representative of most or all autistic syndromes, any observed relationships between biological markers and severity ratings would not be expected to relate to the cause of the condition, rather to modifiers or epiphenomena, and, therefore, should be interpreted cautiously. Moreover, these data underscore alternate prospects for biomarker discovery in which neural, genetic, and physiologic signatures are linked to endophenotypic contributors to autistic syndromes (see Pohl et al 2019;Constantino 2019) within the normal range of the population distribution.…”

Quantitative trait variation in ASD probands and toddler sibling outcomes at 24 months

“…Findings from the present report echo this work by demonstrating that it is ASD endophenotypes (language, adaptive behavior) and not ASD traits that are associated among concordant pairs. Taken together, this work emphasizes the importance of investigating the contribution of familial genetics to early precursor behavioral traits rather than to the diagnosis of ASD itself or to behaviors that emerge well after symptoms are evident [48].…”

“…There is growing support for the hypothesis that ASD, which is both polygenic [3][4][5] and pleiotropic [45,46] in nature, may be traceable to early-emerging developmental endophenotypes that are both specific and nonspecific to ASD [47,48]. This is evidenced by a body of work documenting that sensory, motor, and language behaviors are altered in the first year of life, prior to the onset of ASD symptoms [48,49]. The need to explore genetic associations early, prior to symptom onset, is well illustrated in two recent twin studies.…”