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Variants in cis-regulatory elements link the noncoding genome to human pathology; however, detailed analytic tools for understanding the association between cell-level brain pathology and noncoding variants are lacking. CWAS-Plus, adapted from a Python package for category-wide association testing (CWAS), enhances noncoding variant analysis by integrating both whole-genome sequencing (WGS) and user-provided functional data. With simplified parameter settings and an efficient multiple testing correction method, CWAS-Plus conducts the CWAS workflow 50 times faster than CWAS, making it more accessible and user-friendly for researchers. Here, we used a single-nuclei assay for transposase-accessible chromatin with sequencing to facilitate CWAS-guided noncoding variant analysis at cell-type-specific enhancers and promoters. Examining autism spectrum disorder WGS data (n = 7280), CWAS-Plus identified noncoding de novo variant associations in transcription factor binding sites within conserved loci. Independently, in Alzheimers disease WGS data (n = 1087), CWAS-Plus detected rare noncoding variant associations in microglia-specific regulatory elements. These findings highlight CWAS-Pluss utility in genomic disorders and scalability for processing large-scale WGS data and in multiple-testing corrections. CWAS-Plus and its user manual are available at https://github.com/joonan-lab/cwas/ and https://cwas-plus.readthedocs.io/en/latest/, respectively.

Background : Whole-genome sequencing (WGS) analyses have found higher genetic burden in autistic females compared to males, supporting higher liability threshold in females. However, genomic evidence of sex differences has been limited to European ancestry to date and little is known about how genetic variation leads to autism-related traits within families across sex. Methods: To address this gap, we present WGS data of Korean autism families (n = 2255) and a Korean general population sample (n = 2500), the largest WGS data of East Asian ancestry. We analyzed sex differences in genetic burden and compared with cohorts of European ancestry (n = 15,839). Further, with extensively collected family-wise Korean autism phenotype data (n = 3730), we investigated sex differences in phenotypic scores and gene-phenotype associations within family. Results: We observed robust female enrichment of de novo protein-truncating variants in autistic individuals across cohorts. However, sex differences in polygenic burden varied across cohorts and we found that the differential proportion of comorbid intellectual disability and severe autism symptoms mainly drove these variations. In siblings, males of autistic females exhibited the most severe social communication deficits. Female siblings exhibited lower phenotypic severity despite the higher polygenic burden than male siblings. Mothers also showed higher tolerance for polygenic burden than fathers, supporting higher liability threshold in females. Conclusions: Our findings indicate that genetic liability in autism is both sex- and phenotype-dependent, expanding the current understanding of autism's genetic complexity. Our work further suggests that family-based assessments of sex differences can help unravel underlying sex-differential liability in autism. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine genetic variations underlying the early neurodevelopmental outcome of developmental disabilities (DDs). The study cohort consisted of 191 children with DDs. Diagnosis was assessed at baseline and at the index age (72–84 months). Exome sequencing was conducted and putative risk variants were identified. According to the diagnostic improvement, children were categorized into the improvement group (n = 19) and the non-improvement group (n = 172). Compared to the non-improvement group, the improvement group had lower number of risk variants in known DD genes and haploinsufficient genes, and lower number of overall putative risk variants. Our results may serve as a preliminary basis for developing a model that informs clinical outcome by sequencing analysis. [ABSTRACT FROM AUTHOR]

Allium ulleungense (AU) and A. microdictyon (AM) are valuable medicinal and edible vegetables, referred to as mountain garlic in Korea. The identification of AU, AM and a neighboring species A. ochotense (AO) is difficult because of their morphological similarities. We collected samples from three species and 46 cultivated collections to understand the genetic diversity of these valuable Allium species. Among them, we sequenced six collections, including three species and three cultivating collections to obtain data from the plastid genome (plastome) and nuclear 45S ribosomal DNA (nrDNA) for super-barcoding. The AM and AO showed around 60 single nucleotide polymorphisms (SNPs) and 39 Insertion/Deletion (InDels) in the plastome but no variations in the nrDNA sequences. Conversely, the AU and AM showed more than 170 SNPs and 80 InDels in the plastomes, and 20 SNPs and 1 InDel were found in the 45S nrDNA sequences. Among the three cultivating collections, one TB collection was determined to be the AU type in both plastome and nrDNA sequences. However, the other two collections, JB and SA, showed the AM type plastome but were heterozygous in the 45S nrDNA sequences, indicating both AU and AM types (putative AM x AU hybrid). Ten molecular markers were developed based on sequence variations to identify these three species and assess their genetic diversity. A total of 49 collections were genotyped using the ten developed markers and classified into five groups: 14 AU, 22 AM, 1 AO, 3 putative AM x AU hybrids, and 9 putative AU x AM hybrid collections. Super-barcoding with plastomes and nrDNAs revealed the genetic diversity of the three Allium species and putative hybrids between species. The newly developed markers will facilitate species and hybrid identification, thereby benefiting marker-assisted molecular breeding of Allium species. [ABSTRACT FROM AUTHOR]