Association of Polygenic Liability for Autism With Face-Sensitive Cortical Responses From Infancy

This cohort study investigates whether N290 latency to faces vs nonfaces is associated with autism polygenic scores and cross-disorder polygenic scores in infants with and without a family history of autism.

Autism is a heritable condition affecting 1% of people worldwide. Despite a pressing need for early intervention, the developmental paths through which genetic variants are associated with emerging behavioral symptoms in infancy remain opaque. The latency of the N170 event-related potential response to faces is replicably altered in individuals with autism 1 and has potential as a stratification biomarker for prognostic social functioning. 2 The N170 precursor (N290) to faces vs nonfaces is also altered prior to symptom emergence in infants subsequently diagnosed with autism. 3 These early differences in brain processing represent a plausible developmental mechanism linking genetic liability and behavioral autism symptoms. We investigated whether N290 latency to faces vs nonfaces is associated with autism polygenic scores and cross-disorder polygenic scores in infants with and without a family history of autism.
Methods | In this cohort study, 104 infants with and without a family history of autism provided DNA and participated in an electroencephalography (EEG) task 3 presenting face and nonface images as part of a longitudinal prospective study (the British Autism Study of Infant Siblings [BASIS]). Diagnostic assessments at age 3 years determined whether infants with a family history of autism were diagnosed with autism, showed typical development, or showed other signs of atypical development (Table). Ethical approval was obtained from the Health Research Authority of the English National Health Service. Parents gave written informed consent.
Infants viewed face or nonface (scrambled pixels of the face) images while brain electrical activity was measured continuously with a 128-channel Hydrocel Sensor Net System (Electrical Geodesics Inc). N290 latency was extracted for each condition (220 to 319 milliseconds; more than 10 goodquality EEG trials; mean of 19 occipitotemporal electrodes), and the difference in N290 latency between face and nonface stimuli was computed (face-nonface [F-N] N290 latency).
Genome-wide genotype data were obtained from saliva and buccal cheek-swab DNA. 4 Standardized polygenic scores were calculated using PRSice-2 software in R version 3.6.3 (The R Foundation) for 234 unrelated infants of European ancestry, assigned by the investigators based on principal component analysis on a combined sample of infants' and Hapmap3 genotypes. Autism polygenic scores and cross-disorder polygenic scores were generated using the Autism 5 and Cross-Disorder 6 European-based genome-wide association studies (GWAS) at a range of P value thresholds (.001 < threshold P ≤ 1). Linkage disequilibrium estimation for clumping (r 2 < 0.1; 250-kilobase distance from index variant) was based on the 1000 Genomes Project reference panel. Five ancestry principal components were included as covariates.

Supplemental content
Regression analyses tested the association between F-N N290 latency and autism polygenic scores and crossdisorder polygenic scores at the GWAS P value thresholds that explained the highest variance (Nagelkerke R 2 ) in infants with autism and a family history of autism and those with atypical development (whether autism or other). Model fit improvement was tested using χ 2 when adding autism polygenic scores to the logistic model that tested the association of F-N N290 latency with autism. Tests were 2-tailed and significance was set at P < .05. Details on diagnostic assessment, EEG, and genetic data preprocessing are available in the eMethods in the Supplement and online at https://github.com/annagui/ PGS_EEG.
Discussion | Altered cortical responses to social vs nonsocial stimuli in infancy may be one brain processing pathway through which genetic liability leads to behavioral autism  symptoms and may suggest a suitable target for early identi-