Recent CIG publications Archive

Genome Med. 2022 Aug 11;14(1):89. doi: 10.1186/s13073-022-01088-w.

Limited evidence for blood eQTLs in human sexual dimorphism

Eleonora Porcu ^1 2 3, Annique Claringbould ^4 5, Antoine Weihs ⁶, Kaido Lepik ^7 8, BIOS Consortium; Tom G Richardson ^9 10, Uwe Völker ^11 12, Federico A Santoni ^13 14, Alexander Teumer ^12 15, Lude Franke ⁴, Alexandre Reymond ^# 16, Zoltán Kutalik ^{# 17 18 19}

Abstract

Background: The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits.

Methods: To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs.

Results: Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis-eQTLs. Compensatory effects may further hamper their detection.

Conclusions: Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs.

• PMID: 35953856
• PMCID: PMC9373355
• DOI: 10.1186/s13073-022-01088-w

Curr Opin Genet Dev. 2022 Aug 5;76:101963. doi: 10.1016/j.gde.2022.101963. Online ahead of print.

Exploring conditional gene essentiality through systems genetics approaches in yeast

Núria Bosch-Guiteras ¹, Jolanda van Leeuwen ²

Abstract

An essential gene encodes for a cellular function that is required for viability. Although viability is a straightforward phenotype to analyze in yeast, defining a gene as essential is not always trivial. Gene essentiality has generally been studied in specific laboratory strains and under standard growth conditions, however, essentiality can vary across species, strains, and environments. Recent systematic studies of gene essentiality revealed that two sets of essential genes exist: core essential genes that are always required for viability and conditional essential genes that vary in essentiality in different genetic and environmental contexts. Here, we review recent advances made in the systematic analysis of gene essentiality in yeast and discuss the properties that distinguish core from context-dependent essential genes.

• PMID: 35939967
• DOI: 10.1016/j.gde.2022.101963

BMJ Open Diabetes Res Care. 2022 Aug;10(4):e002890. doi: 10.1136/bmjdrc-2022-002890.

The 12-Item Hypoglycemia Impact Profile (HIP12): psychometric validation of a brief measure of the impact of hypoglycemia on quality of life among adults with type 1 or type 2 diabetes

Melanie Broadley ¹, Hannah Chatwin ², Uffe Søholm ², Stephanie A Amiel ³, Jill Carlton ⁴, Bastiaan E De Galan ^5 6, Christel Hendrieckx ^7 8, Rory J McCrimmon ⁹, Søren E Skovlund ^10 11, Frans Pouwer ^2 12, Jane Speight ^2 7 8, Hypo-RESOLVE Consortium

Abstract

Introduction: The aim of this study was to determine the psychometric properties of the 12-Item Hypoglycemia Impact Profile (HIP12), a brief measure of the impact of hypoglycemia on quality of life (QoL) among adults with type 1 (T1D) or type 2 diabetes (T2D).

Research design and methods: Adults with T1D (n=1071) or T2D (n=194) participating in the multicountry, online study, ‘Your SAY: Hypoglycemia’, completed the HIP12. Psychometric analyses were undertaken to determine acceptability, structural validity, internal consistency, convergent/divergent validity, and known-groups validity.

Results: Most (98%) participants completed all items on the HIP12. The expected one-factor solution was supported for T1D, T2D, native English speaker, and non-native English speaker groups. Internal consistency was high across all groups (ω=0.91-0.93). Convergent and divergent validity were satisfactory. Known-groups validity was demonstrated for both diabetes types, by frequency of severe hypoglycemia (0 vs ≥1 episode in the past 12 months) and self-treated episodes (<2 vs 2-4 vs ≥5 per week). The measure also discriminated by awareness of hypoglycemia in those with T1D.

Conclusions: The HIP12 is an acceptable, internally consistent, and valid tool for assessing the impact of hypoglycemia on QoL among adults with T1D. The findings in the relatively small sample with T2D are encouraging and warrant replication in a larger sample.

Keywords: hypoglycemia; psychometrics; psychosocial issues; quality of life.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

• PMID: 35977753
• DOI: 10.1136/bmjdrc-2022-002890

Cell. 2022 Aug 4;185(16):3041-3055.e25. doi: 10.1016/j.cell.2022.06.036. Epub 2022 Aug 1.

A cross-disorder dosage sensitivity map of the human genome

Ryan L Collins ¹, Joseph T Glessner ², Eleonora Porcu ³, Maarja Lepamets ⁴, Rhonda Brandon ⁵, Christopher Lauricella ⁵, Lide Han ⁶, Theodore Morley ⁶, Lisa-Marie Niestroj ⁷, Jacob Ulirsch ⁸, Selin Everett ⁹, Daniel P Howrigan ¹⁰, Philip M Boone ¹¹, Jack Fu ¹², Konrad J Karczewski ¹⁰, Georgios Kellaris ¹³, Chelsea Lowther ¹², Diane Lucente ¹⁴, Kiana Mohajeri ¹⁵, Margit Nõukas ⁴, Xander Nuttle ¹², Kaitlin E Samocha ¹⁶, Mi Trinh ¹⁷, Farid Ullah ¹³, Urmo Võsa ¹⁸, Epi25 Consortium; Estonian Biobank Research Team; Matthew E Hurles ¹⁷, Swaroop Aradhya ⁵, Erica E Davis ¹³, Hilary Finucane ¹⁰, James F Gusella ⁹, Aura Janze ⁵, Nicholas Katsanis ¹³, Ludmila Matyakhina ⁵, Benjamin M Neale ¹⁰, David Sanders ¹⁹, Stephanie Warren ⁵, Jennelle C Hodge ²⁰, Dennis Lal ²¹, Douglas M Ruderfer ²², Jeanne Meck ⁵, Reedik Mägi ¹⁸, Tõnu Esko ¹⁸, Alexandre Reymond ²³, Zoltán Kutalik ²⁴, Hakon Hakonarson ², Shamil Sunyaev ²⁵, Harrison Brand ²⁶, Michael E Talkowski ²⁷Collaborators, Affiliations expand

Abstract

Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the properties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 triplosensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will provide broad utility for human disease research and clinical genetics.

• PMID: 35917817
• DOI: 10.1016/j.cell.2022.06.036

PLoS Biol. 2022 Jul 22;20(7):e3001705. doi: 10.1371/journal.pbio.3001705. eCollection 2022 Jul.

Sweet sensors support stressed cell survival

Nathaniel J Himmel ¹, Richard Benton ¹

Abstract

Gustatory receptors (Grs) are well known for their functions in sensory neurons in detecting food and toxins. An intriguing new study in PLOS Biology provides evidence for a role for Grs in Drosophila epithelia in protecting stressed cells from proteotoxicity.

• PMID: 35867663
• PMCID: PMC9307178
• DOI: 10.1371/journal.pbio.3001705

Front Pharmacol. 2022 Jul 11;13:902047. doi: 10.3389/fphar.2022.902047. eCollection 2022.

Peroxisomal Proliferator-Activated Receptor β/ δ Deficiency Induces Cognitive Alterations

Triana Espinosa-Jiménez ^1 2 3, Oriol Busquets ⁴, Amanda Cano ^2 5 6 7, Elena Sánchez-López ^2 5 6 8, Ester Verdaguer ^2 3 9, Antoni Parcerisas ¹⁰, Jordi Olloquequi ¹¹, Carme Auladell ^2 3 9, Jaume Folch ^2 12, Walter Wahli ^13 14 15, Manuel Vázquez-Carrera ^1 16 17, Antoni Camins ^1 2 3, Miren Ettcheto ^1 2 3

Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ), the most PPAR abundant isotype in the central nervous system, is involved in microglial homeostasis and metabolism, whose disturbances have been demonstrated to play a key role in memory impairment. Although PPARβ/δ function is well-established in metabolism, its contribution to neuronal and specifically memory process is underexplored. Therefore, the aim of the study is to determine the role of PPARβ/δ in the neuropathological pathways involved in memory impairment and as to whether a risk factor implicated in memory loss such as obesity modulates neuropathological markers. To carry out this study, 6-month-old total knock-out for the Ppard gene male mice with C57BL/6X129/SV background (PPARβ/δ^-/-) and wild-type (WT) littermates with the same genetic background were used. Animals were fed, after the weaning (at 21 days old), and throughout their growth, either conventional chow (CT) or a palmitic acid-enriched diet (HFD). Thus, four groups were defined: WT CT, WT HFD, PPARβ/δ^-/- CT, and PPARβ/δ^-/- HFD. Before sacrifice, novel object recognition test (NORT) and glucose and insulin tolerance tests were performed. After that, animals were sacrificed by intracardiac perfusion or cervical dislocation. Different techniques, such as GolgiStain kit or immunofluorescence, were used to evaluate the role of PPARβ/δ in memory dysfunction. Our results showed a decrease in dendritic spine density and synaptic markers in PPARβ/δ^-/- mice, which were corroborated in the NORT. Likewise, our study demonstrated that the lack of PPARβ/δ receptor enhances gliosis in the hippocampus, contributing to astrocyte and microglial activation and to the increase in neuroinflammatory biomarkers. Additionally, alterations in the hippocampal insulin receptor pathway were found. Interestingly, while some of the disturbances caused by the lack of PPARβ/δ were not affected by feeding the HFD, others were exacerbated or required the combination of both factors. Taken together, the loss of PPARβ/δ^-/- affects neuronal and synaptic structure, contributing to memory dysfunction, and they also present this receptor as a possible new target for the treatment of memory impairment.

• PMID: 35899125
• PMCID: PMC9310104
• DOI: 10.3389/fphar.2022.902047