ASD and schizophrenia show distinct developmental profiles in common genetic overlap with population-based social communication difficulties

Abstract

Difficulties in social communication are part of the phenotypic overlap between autism spectrum disorders (ASD) and schizophrenia. Both conditions follow, however, distinct developmental patterns. Symptoms of ASD typically occur during early childhood, whereas most symptoms characteristic of schizophrenia do not appear before early adulthood. We investigated whether overlap in common genetic influences between these clinical conditions and impairments in social communication depends on the developmental stage of the assessed trait. Social communication difficulties were measured in typically-developing youth (Avon Longitudinal Study of Parents and Children, N⩽5553, longitudinal assessments at 8, 11, 14 and 17 years) using the Social Communication Disorder Checklist. Data on clinical ASD (PGC-ASD: 5305 cases, 5305 pseudo-controls; iPSYCH-ASD: 7783 cases, 11 359 controls) and schizophrenia (PGC-SCZ2: 34 241 cases, 45 604 controls, 1235 trios) were either obtained through the Psychiatric Genomics Consortium (PGC) or the Danish iPSYCH project. Overlap in genetic influences between ASD and social communication difficulties during development decreased with age, both in the PGC-ASD and the iPSYCH-ASD sample. Genetic overlap between schizophrenia and social communication difficulties, by contrast, persisted across age, as observed within two independent PGC-SCZ2 subsamples, and showed an increase in magnitude for traits assessed during later adolescence. ASD- and schizophrenia-related polygenic effects were unrelated to each other and changes in trait-disorder links reflect the heterogeneity of genetic factors influencing social communication difficulties during childhood versus later adolescence. Thus, both clinical ASD and schizophrenia share some genetic influences with impairments in social communication, but reveal distinct developmental profiles in their genetic links, consistent with the onset of clinical symptoms.

Figure 1

Genetic correlations between (a) clinical ASD and (b) clinical schizophrenia and SCDC scores during development. Genetic correlations between clinical disorder and rank-transformed SCDC scores in ALSPAC (at 8, 11, 14 and 17 years) were estimated cross-sectionally using LD-score correlation analysis and are shown with their standard errors (shaded). Standard error distributions for SCDC scores across age were approximated using loess. P-values indicate the probability that the true genetic correlation is different from zero (*P⩽0.05, **P⩽0.01). ALSPAC, Avon Longitudinal study of Parents and Children; ASD, autism spectrum disorder; iPSYCH-ASD, iPSYCH-SSI-BROAD Autism project; LD, linkage disequilibrium; PGC, Psychiatric Genomics Consortium; PGC-ASD, ASD collection of the PGC; PGC-SCZ1, Samples of the first PGC mega-analysis of SCZ; PGC-SCZ2i, PGC-SCZ2 samples not analysed within PGC-SCZ1; SCDC, Social Communication Disorder Checklist; SCZ, schizophrenia.

Figure 2

Proportion of variance in SCDC scores explained by polygenic scores for (a) clinical ASD and (b) clinical schizophrenia. Polygenic scores were constructed in ALSPAC based on the largest publicly available samples for ASD (PGC-ASD) and schizophrenia (PGC-SCZ2) as a training set, and then Z-standardised. The proportion of explained phenotypic variance in rank-transformed SCDC scores (adjusted regression R²) is displayed cross-sectionally at 8, 11, 14 and 17 years and given with respect to ASD-PGS (a) and schizophrenia-PGS (b). Nine different P-value thresholds P_T for selecting risk alleles (PGS bins) in clinical samples are displayed. Starred P-values indicate the strength of the association (*P⩽0.05, **P⩽0.01). ALSPAC, Avon Longitudinal study of Parents and Children; ASD, autism spectrum disorder; PGC-ASD, ASD collection of the PGC; PGC, Psychiatric Genomics Consortium; PGC-SCZ2, Samples of the second PGC mega-analysis of SCZ; PGS, polygenic scores; PGS bin, Z-standardised polygenic scores according to threshold P_T; SCDC, Social Communication Disorder Checklist; SCZ, schizophrenia.

Figure 3

Developmental changes in genetic effects of polygenic scores for (a) clinical ASD and (b) clinical schizophrenia on SCDC scores. Polygenic scores (PGS) were constructed in ALSPAC based on the largest publicly available samples for ASD (PGC-ASD) and schizophrenia (PGC-SCZ2) as a training set, and then Z-standardised. A P-value threshold of P_T <0.05 for selecting risk alleles in clinical samples is displayed. Using a mixed Poisson regression framework, longitudinal measures of untransformed SCDC score counts were regressed on ASD-PGS and schizophrenia-PGS simultaneously allowing for changes in genetic effects over time. Repeatedly assessed SCDC score counts in ALSPAC were available at 8, 11, 14 and 17 years of age with individual ages ranging between 7 to 18 years. Genetic effects for ASD-PGS (a) and their 95% confidence intervals (shaded) as well as schizophrenia-PGS (b) and their 95% confidence intervals (shaded) were estimated across development, and show the increase in SCDC log counts per standard deviation in PGS score. A dotted line indicates the P-value of the genetic effect. ALSPAC, Avon Longitudinal study of Parents and Children; ASD, autism spectrum disorder; PGC-ASD, ASD collection of the PGC; PGC, Psychiatric Genomics Consortium; PGC-SCZ2, Samples of the second PGC mega-analysis of SCZ; SCDC, Social Communication Disorder Checklist; SCZ, schizophrenia.