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With polygenic risk score (PRS) for autoimmune type 1 diabetes (T1D), this study identified T1D cases with low T1D PRS and searched for susceptibility loci in these cases. Our hypothesis is that genetic effects (likely mediated by relatively rare genetic variants) of non-mainstream (or non-autoimmune) T1D might have been diluted in the previous studies on T1D cases in general. Two cohorts for the PRS modeling and testing respectively were included. The first cohort consisted of 3302 T1D cases and 6181 controls, and the independent second cohort consisted of 3297 T1D cases and 6169 controls. Cases with low T1D PRS were identified using PRSice-2 and compared to controls with low T1D PRS by genome-wide association (GWA) test. Thirteen novel genetic loci with high imputation quality (Quality Score r 2  > 0.91) were identified of SNPs/SNVs associated with low PRS T1D at genome-wide significance (P ≤ 5.0 × E-08), in addition to 4 established T1D loci, 3 reported loci by our previous study, as well as 9 potential novel loci represented by rare SNVs, but with relatively low imputation quality (Quality Score r 2  < 0.90). For the 13 novel loci, 9 regions have been reported of association with obesity related traits by previous GWA studies. Three loci encoding long intergenic non-protein coding RNAs (lncRNA), and 2 loci involved in N-linked glycosylation are also highlighted in this study., (© 2021. The Author(s).)

Previous studies of attention-deficit hyperactivity disorder (ADHD) have suggested that structural variants (SVs) play an important role but these were mainly studied in subjects of European ancestry and focused on coding regions. In this study, we sought to address the role of SVs in non-European populations and outside of coding regions. To that end, we generated whole genome sequence (WGS) data on 875 individuals, including 205 ADHD cases and 670 non-ADHD controls. The ADHD cases included 116 African Americans (AA) and 89 of European Ancestry (EA) with SVs in comparison with 408 AA and 262 controls, respectively. Multiple SVs and target genes that associated with ADHD from previous studies were identified or replicated, and novel recurrent ADHD-associated SV loci were discovered. We identified clustering of non-coding SVs around neuroactive ligand-receptor interaction pathways, which are involved in neuronal brain function, and highly relevant to ADHD pathogenesis and regulation of gene expression related to specific ADHD phenotypes. There was little overlap (around 6%) in the genes impacted by SVs between AA and EA. These results suggest that SVs within non-coding regions may play an important role in ADHD development and that WGS could be a powerful discovery tool for studying the molecular mechanisms of ADHD.