Polygenic risk for autism spectrum disorder associates with anger recognition in a neurodevelopment-focused phenome-wide scan of unaffected youths from a population-based cohort

Frank R Wendt, Carolina Muniz Carvalho, Gita A Pathak, Joel Gelernter, Renato Polimanti, Frank R Wendt, Carolina Muniz Carvalho, Gita A Pathak, Joel Gelernter, Renato Polimanti

Abstract

The polygenic nature and the contribution of common genetic variation to autism spectrum disorder (ASD) allude to a high degree of pleiotropy between ASD and other psychiatric and behavioral traits. In a pleiotropic system, a single genetic variant contributes small effects to several phenotypes or disorders. While analyzed broadly, there is a paucity of research studies investigating the shared genetic information between specific neurodevelopmental domains and ASD. We performed a phenome-wide association study of ASD polygenetic risk score (PRS) against 491 neurodevelopmental subdomains ascertained in 4,309 probands from the Philadelphia Neurodevelopmental Cohort (PNC) who lack an ASD diagnosis. Our main analysis calculated ASD PRS in 4,309 PNC probands using the per-SNP effects reported in a recent genome-wide association study of ASD in a case-control design. In a high-resolution manner, our main analysis regressed ASD PRS against 491 neurodevelopmental phenotypes with age, sex, and ten principal components of ancestry as covariates. Follow-up analyses included in the regression model PRS derived from brain-related traits genetically correlated with ASD. Our main finding demonstrated that 11-17-year old probands with the highest ASD genetic risk were able to identify angry faces (R2 = 1.06%, p = 1.38 × 10-7, pBonferroni-corrected = 1.9 × 10-3). This ability replicated in older probands (>18 years; R2 = 0.55%, p = 0.036) and persisted after covarying with other psychiatric disorders, brain imaging traits, and educational attainment (R2 = 0.2%, p = 0.019). We also detected several suggestive associations between ASD PRS and emotionality and connectedness with others. These data (i) indicate how genetic liability to ASD may influence neurodevelopment in the general population, (ii) reinforce epidemiological findings of heightened ability of ASD cases to predict certain social psychological events based on increased systemizing skills, and (iii) recapitulate theories of imbalance between empathizing and systemizing in ASD etiology.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Analysis flowchart with relevant research…
Fig 1. Analysis flowchart with relevant research questions in bold text.
Fig 2. Autism PRS association with PNC…
Fig 2. Autism PRS association with PNC phenotypes.
Overview of best-fit models for autism spectrum disorder (ASD) associating with neurodevelopmental phenotypes in adult (AP, Nphenotypes = 324), middle (MP, Nphenotypes = 490), and young (YP, Nphenotypes = 311) probands of the Philadelphia Neurodevelopmental Cohort. (A) Maximum phenotypic variance explained (R2) by the best model fit for each trait given genetic liability to ASD. The dashed horizontal line represents the nominal significance threshold. (B-D) The relationship between binned ASD polygenic risk scores for AP, MP, and YP participants and the most significant phenotype predicted by ASD genetic liability: (B) SIP033 Structural Interview for Prodromal Symptoms: “Has anyone pointed out to you that you are less emotional or connected to people than you used to be?”; (C) PEITANG: Number of correct responses to anger trials during completion of The Penn Emotional Identification Test (PEIT) for recognizing angry emotions; (D) PADT_SAME_PC: Percent of correct responses to test trials with no age difference during completion of the Penn Age Differentiation Test for detecting which face in a face pair appears older. Note the lowest quartile in figures B-D represents the referent.
Fig 3. Predicting emotion recognition with ASD…
Fig 3. Predicting emotion recognition with ASD PRS.
Association between facial emotion capabilities of the middle proband group (ages 11 to 17) of the Philadelphia Neurodevelopmental Cohort using polygenic risk (PRS) for autism spectrum disorder. The x-axis shows correctness and response time for each facial emotion using two neurocognitive instruments: The Penn Emotion Identification Test (shaded colors: original results; tinted colors: results covaried for the effects of PEITANG). Significance is indicated by * for p

Fig 4. Robustness of the ASD and…

Fig 4. Robustness of the ASD and PEITANG relationship.

Association between the ability to recognize…

Fig 4. Robustness of the ASD and PEITANG relationship.
Association between the ability to recognize angry faces in the middle proband group (ages 11–17) using the polygenic risk for autism spectrum disorder (ASD) covaried for age, sex, ten principal components, and the PRS for four brain imaging phenotypes, attention deficit hyperactivity disorder, schizophrenia, and educational attainment. (A) PRS p-value across a range of genome-wide significance (GWS) thresholds; the maximum PRS before and after covarying for all brain and psychiatry traits are labeled. (B) The positive correlation between quartiles of ASD polygenic risk and the number of correct responses to anger recognition trials in the Penn Emotional Intelligence Test; the lowest PRS quartile represents the referent.
Fig 4. Robustness of the ASD and…
Fig 4. Robustness of the ASD and PEITANG relationship.
Association between the ability to recognize angry faces in the middle proband group (ages 11–17) using the polygenic risk for autism spectrum disorder (ASD) covaried for age, sex, ten principal components, and the PRS for four brain imaging phenotypes, attention deficit hyperactivity disorder, schizophrenia, and educational attainment. (A) PRS p-value across a range of genome-wide significance (GWS) thresholds; the maximum PRS before and after covarying for all brain and psychiatry traits are labeled. (B) The positive correlation between quartiles of ASD polygenic risk and the number of correct responses to anger recognition trials in the Penn Emotional Intelligence Test; the lowest PRS quartile represents the referent.

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