Deleterious coding variation associated with autism is consistent across populations, as exemplified by admixed Latin American populations

Abstract

The past decade has seen remarkable progress in identifying genes that, when impacted by deleterious coding variation, confer high risk for autism spectrum disorder (ASD), intellectual disability, and other developmental disorders. However, most underlying gene discovery efforts have focused on individuals of European ancestry, limiting insights into genetic risks across diverse populations. To help address this, the Genomics of Autism in Latin American Ancestries Consortium (GALA) was formed, presenting here the largest sequencing study of ASD in Latin American individuals (n>15,000). We identified 35 genome-wide significant (FDR < 0.05) ASD risk genes, with substantial overlap with findings from European cohorts, and highly constrained genes showing consistent signal across populations. The results provide support for emerging (e.g., MARK2, YWHAG, PACS1, RERE, SPEN, GSE1, GLS, TNPO3, ANKRD17) and established ASD genes, and for the utility of genetic testing approaches for deleterious variants in diverse populations, while also demonstrating the ongoing need for more inclusive genetic research and testing. We conclude that the biology of ASD is universal and not impacted to any detectable degree by ancestry.

Figure 1.. Overview of GALA cohort sites, structure, and ancestry composition.

(a) Pedigree structure of the GALA cohort, comprising 4,717 cases and 10,710 controls. Diamonds represent offspring, probands are shown in gray, and typically-developing siblings in white. (b) Map of GALA collection sites across the Americas. (c) Ancestral composition of individuals from each GALA site based on ADMIXTURE analysis (K = 7). Ancestry components are: AMR (Admixed American, purple), NFE (non-Finnish European, red), AFR (African, orange), MID (Middle Eastern, brown), FIN (Finnish, blue), SAS (South Asian, yellow), and EAS (East Asian, green). AMR samples from the ASC and SPARK are presented in the lower panel.

Figure 2.. Comparison of rare de novo variant counts per sample between ASD probands and unaffected siblings in the GALA cohort.

The average number of rare variants per sample is compared between ASD probands (dark blue, n = 4,450) and unaffected siblings (light blue, n = 1,459) of Admixed American ancestry (AMR). The analysis includes (left) protein truncating variants (PTVs) in highly constrained genes (LOEUF deciles 1–3, 5,363 genes) and less constrained genes (LOEUF deciles 4–10, 12,765 genes), (middle) missense variants categorized by predicted functional severity (MPC ≥ 2 for high severity, 1 ≤ MPC < 2 for moderate severity), and (right) MPC < 1 (for low severity) and synonymous missense variants. Error bars represent 95% confidence intervals.

Figure 3.. Ratio of observed PTVs in NFE vs. AMR ancestries.

The sum of observed protein truncating variants (PTVs) is plotted for Non-Finnish European (NFE) and Admixed American (AMR) populations in gnomAD v2.1.1, scaled to population size and total coding sequence length for each gnomAD LOEUF decile. Population sizes are NFE: 56,885 and AMR: 17,296. LOEUF deciles reflect gene constraint, with lower deciles indicating more constrained genes.

Figure 4.. Manhattan plot of ASD genes identified in Latin American participants.

The plot displays 35 genes identified with a false discovery rate (FDR) threshold of < 0.05 (see Table 1).

Figure 5.. “Lollipop” diagrams illustrating variants identified in ASD-associated genes.

Variants observed in GALA analyses of AMR individuals are marked with pink circles, those found in Fu_COMP individuals are marked with green, and variants found in DECIPHER are in purple. Note that there were two instances of V123Wfs*2 variants in GSE1 in GALA, two instances of R203W in PACS1 in GALA, and 18 such variants in DECIPHER. Figures were generated using the ‘lollipop’ software package (Jay and Brouwer, 2016).