Genetic influence of sequence variants in SCARB1 and ABCA1 genes on major lipid traits: a candidate gene association study

Background: Abnormal lipid-lipoprotein levels are associated with the risk of coronary heart disease (CHD), a major public health problem worldwide. Scavenger receptor class B type 1 (SCARB1) and ATP-binding cassette transporter A1 (ABCA1) play important roles in the reverse cholesterol transport. We aimed to identify genetic variants in two lipid genes, SCARB1 and ABCA1, and elucidated their contribution to major lipid traits in two populations; Non-Hispanic Whites (NHWs) and African Blacks (ABs). Methods: We resequenced mainly the exons and exon-intron boundaries of SCARB1 and ABCA1 genes in 190 individuals (95 NHWs; 95 ABs) with extreme high-density lipoprotein cholesterol (HDL-C) levels, followed by genotyping of selected variants in the entire sample (623 NHWs; 788 ABs). Lipid associations were evaluated by multiple analyses. Results: Initial sequencing identified 105 SCARB1 (44/NHWs; 83/ABs) and 404 ABCA1 variants, including 58 novel ones (21 SCARB1; 37 ABCA1). Among genotyped variants, 159 SCARB1 (69/NHWs; 137/ABs) and 182 ABCA1 variants passed quality controls and were tested for associations. Gene-based tests revealed associations (P <0.05) of SCARB1 with HDL-C and apolipoprotein B (apoB), while ABCA1 demonstrated association with triglycerides (TG). Eleven common SCARB1 variants were nominally associated (P <0.05) with HDL-C or apoB in single-site analyses, and four of them (3/apoB/NHWs; 1/HDL-C/ABs) survived after multiple testing correction. The best signal of SCARB1 was rs4765615 (apoB/P = 0.0059) in NHWs and rs11057851 (HDL-C/P = 0.0043) in ABs. Twenty-one common ABCA1 variants were nominally associated with TG, and 16 remained significant after multiple testing correction. The best signal of ABCA1 with TG was rs2066716 (p.Thr14217Thr; P = 0.0016) in NHWs. A group of rare SCARB1 variants (frequency ≤1%) were associated with apoB (P = 0.0284) in NHWs, and HDL-C (P = 0.0478) in ABs. Several haplotypes and regions of SCARB1 and ABCA1 genes showed associations (global P <0.05) with lipid levels. Public health relevance: Our findings demonstrate the genetic contribution of common and rare SCARB1 and ABCA1 variants to the regulation of lipoprotein-lipid levels in the general population, supporting the roles of SCARB1 and ABCA1 genes in lipid metabolism. Further investigations of these two genes may lead to the development of potential therapeutic interventions for CHD

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E–09 and 4.10E–18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.publishedVersio

Additional file 12: Figure S5. of Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study

Location and minor allele frequency (MAF) distributions of 137 SCARB1 genotyped variants. Details for each variant are shown in Additional file 9: Table S6. MAF, minor allele frequency; UTR, untranslated region. (TIFF 324 kb

Additional file 8: Figure S3. of Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study

Linkage disequilibrium (LD) plot of 108 SCARB1 common HapMap-YRI tagSNPs. The list of 77 common HapMap-YRI tagSNPs identified by Tagger analysis of variants with minor allele frequency ≥5 % using an r2 cutoff of 0.80 is shown in Additional file 7: Table S5. The degree of shades and values (r2 × 100) in each square of LD plot represent the pairwise correlations: black indicating r2 = 1, white indicating r2 = 0, and shade intensity indicating r2 between 0 and 1.LD, linkage disequilibrium; SNP, single nucleotide polymorphism; YRI, Yoruba people of Ibadan from Nigeria. (TIFF 2642 kb

Additional file 1: Table S1. of Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study

Characteristics and lipid profile of the entire sample of 788 African Blacks stratified by sex. (PDF 63 kb

Additional file 18: Table S13. of Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study

RegulomeDB scores and functional assignments of 153 SCARB1 variants. (PDF 149 kb

Additional file 11: Figure S4. of Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study

Linkage disequilibrium (LD) plot of 137 SCARB1 genotyped variants. The list of 87 genotyped common tagSNPs identified by Tagger analysis for variants with minor allele frequency ≥5 % using an r2 cutoff of 0.90 is shown in Additional file 10: Table S7. The degree of shades and values (r2 × 100) in each square of LD plot represent the pairwise correlations: black indicating r2 = 1, white indicating r2 = 0, and shade intensity indicating r2 between 0 and 1.LD, linkage disequilibrium; SNP, single nucleotide polymorphism. (TIFF 3095 kb

Additional file 14: Table S9. of Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study

Single-site association results for 136 SCARB1 genotyped variants with HDL-C. (PDF 689 kb