Evaluation of the Common Genetic Architecture of Problematic Peer Relationships

Background:   Peer interaction plays an important role in the development of social competence, and problematic childhood peer relationships often precede later maladjusted behaviour. Some links between early peer rejection and later maladaptive functioning however might be mediated through an underlying pathology. This includes impairments in social interaction skills, which are characteristic and heritable symptoms of the autistic dimension including Autism Spectrum disorders (ASD).

Objectives: Our study i) aimed to investigate genetic influences contributing to impaired peer relationships during childhood and adolescence, and ii) to identify population-based single SNP signals, which also contribute to risk for ASD.

Methods: Heritability was estimated using ≤7366 UK twin pairs (Twins Early Development Study, TEDS) with parent-report on peer problems at  4, 7, 9 and 11 years. A genome-wide analysis was conducted within N≤6000 children from a UK birth-cohort (Avon Longitudinal Study of Parents and children, ALSPAC) with parent-report on peer problems at 4, 7, 8, 10, 12, 13 and 17 years. Association signals were followed-up within independent children from TEDS (N≤2837) and were also investigated in the Autism Genetic Research Exchange (AGRE) sample (793 ASD pedigrees) and the Autism Case-Control cohort (ACC, 1204 ASD subjects, 6491 control subjects).

Results: Problematic peer relationships are substantially heritable throughout early/middle childhood (h²=0.60-0.71). During this developmental period however, there might be only few measurable common additive  genetic effects (DNA-based h²≤0.12). During later adolescence by contrast the proportion of measurable common additive genetic effects is increasing (DNA-based h²=0.14-0.27). Two  population-based signals in ALSPAC  (rs6451614 at 5p13.1 near GHR, P_17years=9.6x10^-6, rs7873232 at 9p24.2 near GLIS3 and RFX3, P_13years=7.3x10^-6) were identified during later adolescence  (out of 50 independent signals with P<10^-5 across all time-points) and showed evidence for replication in AGRE  (rs6451614 P=0.00058, rs7873232 P=0.0030), but not the ACC (rs1858136, proxy for rs6451614, r²=0.88, P=0.69; rs7873232 P=0.99). No comparable effect was observed within TEDS children spanning a younger age-range. Longitudinal modelling confirmed that genetic effects at both rs6451614 and rs7873232 varied across development, and that the underlying associations are complex.

Conclusions:   Common genetic effects contribute to variation in problematic peer relationships, however the influence of measurable common additive genetic effect is strongest in later adolescence. Overlaps with the autistic continuum might be present, but many more samples might be required to reliably identify single associations.