Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/287136

Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia

Curtis, D.
View original source ↗Export metadata ↓

Abstract

BackgroundThe polygenic risk score (PRS) for schizophrenia, derived from very large numbers of weakly associated genetic markers, has been repeatedly shown to be robustly associated with schizophrenia in independent samples and also with other diseases and traits.\n\nAimsTo explore the distribution of the schizophrenia PRS in subjects of different ancestry.\n\nMethodThe schizophrenia PRS derived from the large genome-wide association study carried out by the Psychiatric Genetics Consortium was calculated using the downloaded genotypes of HapMap subjects from eleven different ancestral groups. It was also calculated using downloaded genotypes of European schizophrenia cases and controls from the CommonMind Consortium.\n\nResultsThe PRS for schizophrenia varied significantly between ancestral groups (p < 2*10-16) and was much higher in African than European HapMap subjects. The mean difference between these groups was ten times as high as the mean difference between European schizophrenia cases and controls. The distributions of scores for African and European subjects hardly overlapped.\n\nConclusionsThe PRS cannot be regarded as simply a measure of the polygenic contribution to risk of schizophrenia and clearly contains a strong ancestry component. It is possible that this could be controlled for to some extent by incorporating principal components as covariates but doubts remain as to how it should be interpreted. The PRS derived from European subjects cannot be applied to non-Europeans, limiting its potential usefulness and raising issues of inequity. Previous studies which have used the PRS should be re-examined in the light of these findings.\n\nDeclaration of interestThe author declares he has no conflict of interest.

Source connections

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Curtis, D.. 2018-03-23. Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia. https://doi.org/10.1101/287136

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Mapping, stacking and characterization of a novel resistance haplotype against GpaVvrn-virulent Globodera pallida derived from wild potato relative Solanum brevicaule

Potato production is threatened by pests and pathogens. Among the most harmful are the potato cyst nematodes (PCN), including Globodera pallida. The major control measures are potato cultivars harbouring resistance genes. However, virulent nematode populations are breaking through the most broadly applied resistance genes, and therefore novel resistance genes are required to keep control of G. pallida. In this study we map a resistance locus in wild potato relative Solanum brevicaule to the bottom of chromosome 11 (42.83 - 42.85 Mb) using a k-mer based bulked segregant analysis and name the resistant haplotype GpaXIbrc. The presence of the GpaXIbrc marker in the potato genome significantly increases resistance against a GpaVvrn-virulent G. pallida population (AMPOP01). Furthermore, the GpaXIbrc haplotype was stacked with three other resistance haplotypes: GpaXItar, GpaVvrn, and GpaIXvrn. Stacking of the novel GpaXIbrc haplotype to these other resistance haplotypes resulted in a significant increase in resistance. The largest effect was seen in combinations with 'major' resistance haplotypes GpaVvrn + GpaIXvrn and GpaXItar + GpaXIbrc. To determine whether we are dealing with a novel allele, the resistance mechanism underlying the GpaXIbrc haplotype was described after performing an in vitro bioassay. The resistance mechanism was different from GpaXIspl as described in literature, which is also localized at the bottom of chromosome 11. Therefore, we conclude that we found a novel resistance allele originating from S. brevicaule.

genetics↗
bioRxiv2026

Cellular context shapes the transcriptomic impact of somatic variants

Somatic SNVs are commonly prioritized by recurrence or sequence annotation, leaving the molecular consequences of private variants unresolved. We developed PrismSNV and Ligo-Seq, a single-cell full-length transcriptome sequencing platform, to quantify transcriptomic displacement associated with within-cell SNV-state toggling. Across 26 samples from three cancer types, more than 60% of candidate SNVs showed significant cell-type-specific displacement with over 30% variation in magnitude. Sequence-based deleteriousness was poorly aligned with cellular displacement, and fewer than 3% of top-displacement SNVs across six tumor types were catalogued in ClinVar. Displacement was strongest in transcriptionally plastic, less differentiated states. Analysis of 655,349 CD4+ T-cell transcriptomes further showed that SNV-gene associations changed in magnitude and sometimes direction during activation. Lack of recurrence or clinical annotation does not imply transcriptomic inertness; variant impact is shaped by cellular context rather than sequence alone, establishing the variant-cell pair as a critical unit for interpreting somatic variation.

genetics↗
bioRxiv2026

Genetic and Epigenetic Landscape of Self-Identified Hispanics/Latino in All Of Us

Human genetic studies still underrepresent many populations, limiting discovery and interpretation of medically relevant variation. Extensive admixture in self-identified Hispanic/Latino populations increases the need for representative reference data and ancestry-aware interpretation of medically relevant variation. We used long-read sequencing to analyze genetic variation, ancestry, and DNA methylation in 1,490 self-identified Hispanic/Latino participants from the All of Us Research Program. We identified 10 million novel variants and more than 100 candidate phenotype associations, with fine-mapping prioritizing structural variants over nearby single-nucleotide variants in more than half. We linked 3,329 tandem repeats to DNA methylation, resolved widespread allele-specific methylation, and identified ancestry-linked regulation across paralogous genes. These results reveal previously inaccessible genetic and regulatory variation and show the value of long-read sequencing for diverse populations.

genetics↗