Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding Information: GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file : Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Network analysis of drug effect on triglyceride-associated DNA methylation

Abstract Background DNA methylation, an epigenetic modification, can be affected by environmental factors and thus regulate gene expression levels that can lead to alterations of certain phenotypes. Network analysis has been used successfully to discover gene sets that are expressed differently across multiple disease states and suggest possible pathways of disease progression. We applied this framework to compare DNA methylation levels before and after lipid-lowering medication and to identify modules that differ topologically between the two time points, revealing the association between lipid medication and these triglyceride-related methylation sites. Methods We performed quality control using beta-mixture quantile normalization on 463,995 cytosine-phosphate-guanine (CpG) sites and deleted problematic sites, resulting in 423,004 probes. We identified 14,850 probes that were nominally associated with triglycerides prior to treatment and performed weighted gene correlation network analysis (WGCNA) to construct pre- and posttreatment methylation networks of these probes. We then applied both WGCNA module preservation and generalized Hamming distance (GHD) to identify modules with topological differences between the pre- and posttreatment. For modules with structural changes between 2 time points, we performed pathway-enrichment analysis to gain further insight into the biological function of the genes from these modules. Results Six triglyceride-associated modules were identified using pretreatment methylation probes. The same 3 modules were not preserved in posttreatment data using both the module-preservation and the GHD methods. Top-enriched pathways for the 3 differentially methylated modules are sphingolipid signaling pathway, proteoglycans in cancer, and metabolic pathways (p values < 0.005). One module in particular included an enrichment of lipid-related pathways among the top results. Conclusions The same 3 modules, which were differentially methylated between pre- and posttreatment, were identified using both WGCNA module-preservation and GHD methods. Pathway analysis revealed that triglyceride-associated modules contain groups of genes that are involved in lipid signaling and metabolism. These 3 modules may provide insight into the effect of fenofibrate on changes in triglyceride levels and these methylation sites

Association of mitochondrial DNA copy number with brain MRI and cognitive function in the TOPMed Program

BackgroundMitochondria are the main energy source for normal neuronal functions. Mitochondrial DNA (mtDNA) copy number (CN), a measure of mtDNA levels in the cell, correlates with cellular energy generating capacity and metabolic status. Previous studies have observed a significant decrease of circulating cell‐free mtDNA content in the cerebrospinal fluid of patients with Alzheimer’s disease (AD). However, it is unknown whether mtDNA CN circulating in the blood is related to AD endophenotypes. We aimed to investigate the cross‐sectional association of mtDNA CN with MRI markers of abnormal brain aging and cognitive function.MethodWe included dementia‐free, multiethnic participants from seven population‐based cohorts with whole‐genome sequencing as part of the Trans‐Omics for Precision Medicine (TOPMed) program. The average mtDNA CN in whole blood was estimated as twice the ratio of the average coverage of mtDNA to the average coverage of the nuclear DNA using fastMitoCalc from mitoAnalyzer. Brain MRI markers included total brain volume, hippocampal volume, and white matter hyperintensities. General cognitive function was derived from at least three distinct cognitive domains using principal component analysis. We related mtDNA CN to AD endophenotypes assessed within 5 years of blood draw per cohort and further performed random‐effects or sample size‐weighted meta‐analyses. Models were adjusted for demographics and vascular risk factors.ResultHigher mtDNA CN was significantly associated with better general cognitive function (P‐values<0.05) in four cohorts after adjusting for age, sex, batch effect, self‐reported race/ethnicity, the time between blood draw and MRI/Cognitive evaluation, cohort‐specific variables, and education (Figure 1). Meta‐analysis across all cohorts confirmed and strengthened the significant association between mtDNA CN and general cognitive function (n=11,021, Beta=0.046, SE=0.01, P‐value=0.0002). Additional adjustment for diabetes, hypertension, hyperlipidemia, and obesity led to similar results (Beta=0.043, SE=0.01, P‐value=0.002). We observed no significant associations between mtDNA CN and brain MRI markers.ConclusionThis study suggests that higher mtDNA CN is cross‐sectionally associated with better general cognitive function in a large sample from diverse communities across the US, providing novel findings that support the role of mtDNA in healthy brain aging. Additional analyses are underway to relate mtDNA CN to AD endophenotypes prospectively and to incident dementia.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171549/1/alz056243.pd

Assessing whole genome sequencing variation for Alzheimer’s disease in 4707 individuals from the Alzheimer’s Disease Sequencing Project (ADSP)

Background The Alzheimer’s Disease Sequencing Project (ADSP) seeks to identify genomic variants contributing to increased risk of and/or protection from Alzheimer’s disease (AD) in multi‐ethnic populations. Here we report on statistical modeling considerations and results from 4707 diverse individuals including 2076 non‐Hispanic White, 1030 Black, 1304 Hispanic, and 297 of other ancestry with whole genome sequencing (WGS) in the ADSP. Methods A total of 4789 individuals were sequenced across 4 sequencing centers and 2 sequencing platforms. Joint calling was carried out by the ADSP data coordinating center GCAD. We evaluated a series of models to explore technical covariate adjustment related to study, sequencing center, and platform and then performed single variant association analysis for AD status adjusting for principal components associated with AD, technical covariates, and a genetic relatedness matrix, limiting to variants with a minor allele count > 30 and a missingness rate ≤ 10%. We also performed gene‐based association of rare (both MAF < 1% and MAF < 5%) coding variants. Results After quality control, we included over 95 million variants across 4707 individuals (2209 cases, 2498 controls). We replicated association at the APOE locus and identified a locus on chromosome 15 that has a suggestive association with AD status (freq = 0.8%, p‐value = 1 × 10−7). Despite joint genotype calling, adjustment for study, sequencing center and platform are necessary to control type‐I error. In gene‐based tests, we found evidence (p < 0.05) of association for 4 of 8 AD candidate genes with low‐frequency or rare variant associations implicated for AD (TREM2, ABI3, SORL1, and MAPT) as well as suggestive associations (P < 5 × 10−5) for seven genes (ZGRF1 on chr4; C1RL on chr12; NAA30 on chr14; NIPA2 on chr15; and ABCC3, BIRC5 and HIC1 on chr17). Conclusion We explored covariate models for the WGS data from ADSP and established that despite joint calling, it is necessary to account for technical effects in the model. We found suggestive novel associations with AD status that will require confirmation