Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/170241

Exploring repositioning opportunities and side-effects of statins: a Mendelian randomization study of HMG-CoA reductase inhibition with 55 complex traits

So, H.-C.
View original source ↗Export metadata ↓

Abstract

Statin is one of the most commonly prescribed medications worldwide. Besides reduction of cardiovascular risks, statins have been proposed for the prevention or treatment of other disorders, but results from clinical studies are mixed. There are also controversies concerning the adverse effects caused by statins.\n\nIn this study we employed a Mendelian randomization (MR) approach across a wide range of complex traits to explore repositioning opportunities and side-effects of statins. MR is analogous to a \"naturalistic\" randomized controlled trial (RCT), which is much less susceptible to confounding and reverse causation as compared to observational studies.\n\nWe employed two genetic instruments (rs12916 and rs17238484) in the HMGCR gene which have been shown to provide reliable estimates of the risk of statins on type 2 diabetes and weight gain. We observed in the single- and joint-SNP analysis that low density lipoprotein cholesterol (LDL-C) reduction from HMG-CoA reductase inhibition results in increased depressive symptoms. This finding appeared to be supported by nominally significant results of raised major depression risk in single-SNP MR analysis of rs17238484, and analyses using LDL-C as the exposure. Several other outcomes also reached nominal significance (p < 0.05) in single- or joint-SNP analyses; for example, we observed causal associations of LDL-C lowering from HMG-CoA reductase inhibition with reduced risks of schizophrenia, anorexia nervosa, Alzheimer disease, Parkinson disease, as well as increased forearm bone mineral density, sleep duration and extreme longevity (highest q-value = 0.289). We also found evidence of casual relationships of LDL-C levels with schizophrenia, anorexia, sleep duration and longevity, following the same association directions as in analyses of HMGCR variants. These findings were at least partially supported by previous clinical studies. We did not observe associations with cognitive test profiles, renal outcomes, autoimmune diseases or cancers. While MR has its limitations and our findings remain to be confirmed in further studies, this work demonstrates the potential of a phenome-wide approach to reveal novel therapeutic indications and unknown drug side-effects.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

So, H.-C.. 2017-07-30. Exploring repositioning opportunities and side-effects of statins: a Mendelian randomization study of HMG-CoA reductase inhibition with 55 complex traits. https://doi.org/10.1101/170241

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↗