Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/762419

From rare Copy Number Variations to biological processes in ADHD

Harich, B.·van der Voet, M.·Klein, M.·Fenckova, M.·Cizek, P.·Franke, B.·Schenck, A.
View original source ↗Export metadata ↓

Abstract

AimAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.\n\nMethodsWe combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.\n\nResultsWe localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26, POLR3C and RBFOX1 were also supported by common genetic variants.\n\nConclusionsIntegration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Harich, B., van der Voet, M., Klein, M., Fenckova, M., Cizek, P., Franke, B., Schenck, A.. 2019-09-16. From rare Copy Number Variations to biological processes in ADHD. https://doi.org/10.1101/762419

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Genetic diversity of endangered Acropora spp. corals in Bonaire: implications for restoration and gene banking

Species restoration is a valuable tool to combat biodiversity loss. However, maintaining genetic diversity in species restoration is challenging, particularly for species that can reproduce asexually, such as plants and corals, because a seemingly diverse collection of individuals could be composed of many clones of a few genotypes. Caribbean elkhorn and staghorn corals (Acropora palmata, A. cervicornis) are critically endangered reef-building corals that are a major target for restoration. To better understand the genetic diversity of an Acropora spp. restoration program and interpret local population genetic structure, we conducted microsatellite genotyping on the gene banks of 35 A. palmata lineages and 25 A. cervicornis lineages maintained by Reef Renewal Foundation Bonaire (RRFB) in the Caribbean Netherlands. We found that RRFB had high genotypic richness for A. palmata (0.971) and A. cervicornis (1.0) and estimated that they captured 88.9% and 74.7% of Bonaires microsatellite asymptotic allelic diversity, respectively. Compared to populations of Acropora spp. studied in other locations across the Caribbean, A. palmata in Bonaire had relatively low expected heterozygosity, while A. cervicornis was greater than approximately half of other populations. Across Bonaire and for both coral species, we did not find evidence for genetic structuring among spatially separated subpopulations, indicating that both species are likely well-connected around the island. Together, these results demonstrate the effectiveness of RRFBs strategies to capture high genetic diversity and can be used to inform future initiatives on coral sexual breeding and assisted gene flow beyond Bonaire.

genetics↗
bioRxiv2026

Unravelling genomic and environmental contributions to nitrogen-use efficiency in tropical maize through Bayesian causal forests

Nitrogen fertilisation is one of the largest variable input costs in maize production, and genotypes differ in how efficiently they convert added nitrogen into yield. Breeding for nitrogen-use efficiency therefore depends on knowing not only the average response of the crop to nitrogen but how that response varies across genotypes and environments. We frame this as a problem of causal inference and estimate the effect of an ideal versus low nitrogen regime on three maize traits jointly (grain yield, plant height and ear height) using a multivariate Bayesian causal forest. To our knowledge, this is among the first studies to quantify the effect of nitrogen in a genotyped breeding panel as a formally identified causal quantity, estimated from a designed contrast within the potential-outcomes framework, rather than as the genotype-environment association that genomic selection and association mapping report. The trial suits a causal reading: 614 single-cross hybrids were grown under both nitrogen levels in adjacent plots sharing weather and soil, so nitrogen was assigned by design rather than confounded with genotype or environment, and the estimated propensity score was close to 0.5. The leading principal components of the additive genomic relationship matrix were placed in the moderator set, so that both the baseline outcome and the treatment effect could vary with genomic background. Ideal nitrogen raised all three traits (grain yield +0.59, 95% credible interval 0.51 to 0.67; plant height +0.095; ear height +0.044, in adjusted-phenotype units). The heterogeneity of the effect was almost entirely environmental, with a small genotypic component and negligible genotype-by-environment interaction; the posterior credible interval of the effect was wider than the spread among genotypes, so differences in responsiveness among hybrids were only weakly resolved. Reading the two tree ensembles separately indicated that genomic background governs the yield level while climate governs the response to nitrogen, the leading genomic contribution being a single axis. A reaction-norm variance decomposition and cross-validated prediction corroborated this reading. A multivariate causal forest with genomic moderators, read through its two ensembles and reported with posterior uncertainty, is a suitable and transparent tool for studying nitrogen response in breeding material.

genetics↗
bioRxiv2026

X-Chromosomal STR-based analysis of genetic diversity, structure, and phylogeny in the Sri Lankan Vedda population

The Vedda people are regarded as the direct descendants of Sri Lanka's Mesolithic hunter-gatherers and represent one of South Asia's oldest surviving indigenous populations. X-chromosomal short tandem repeat (X-STR) analysis provides a powerful framework to examine their genetic distinctiveness, as the X chromosome exhibits sex-biased biparental inheritance and greater sensitivity to demographic and evolutionary forces compared to autosomal markers. However, no X-STR-based genetic investigations have yet been conducted on this population. In the present study, we successfully genotyped 50 unrelated Veddas individuals using a recently developed 16 X-STR multiplex PCR system optimized for Sri Lankan populations. Our analyses revealed a statistically significant genetic differentiation (2.43%) between the Veddas and the principal local ethnic groups; Sinhalese, Sri Lankan Tamils, Indian Tamils, and Moors exceeding previous estimates based on autosomal STR markers. Comparative analysis with 32 global populations positioned the Veddas as a genetically distinct and isolated group, separated from clusters representing South Asians, Europeans, Middle Easterners, and other indigenous populations such as Australian Aboriginals, Bhil Indians, and Kedayans, emphasizing their unique genetic heritage. Reduced allelic (115) and haplotype (62) counts, alongside significant linkage disequilibrium detected among eight pairs of X-STR loci, reflect the influence of genetic drift within this small, endogamous, and historically isolated population. These findings highlight the evolutionary and demographic distinctiveness of the Veddas and provide essential baseline data for future population genomic studies. Furthermore, the demonstrated high discriminatory power of the 16 X-STR loci supports their continued application in population genetics and anthropological research within this unique community.

genetics↗