Pleiotropic genetic architecture and novel loci for C-reactive protein levels

Koskeridis, Fotios; Εvangelou, Εvangelos; Said, Saredo; Boyle, Joseph J.; Elliott, Paul; Dehghan, Abbas; Tzoulaki, Ioanna

doi:10.1038/s41467-022-34688-6

Cited by 17 publications

(14 citation statements)

References 37 publications

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“…The BBSome complex is a well-replicated causative protein marker for obesity 53 and highly relevant to the HPA-axis activity by being involved in transducing leptin signals in hypothalamic neurons 54,55 . Consistent with the top CpG site, other sites, such as cg02948555 and cg10604091, mapped to genes associated with C-reactive protein (CRP) 8,56 . CRP is one of the most well-studied predictors of vulnerability to depression 57 and persistence of depressive symptoms 58 .…”

Section: Discussionmentioning

confidence: 88%

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

Shen,

Barbu,

Caramaschi

et al. 2023

Preprint

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Major Depression (MD) is a leading cause of global disease burden, and both experimental and population-based studies suggest that differences in DNA methylation (DNAm) may be associated with the condition. However, previous DNAm studies have not so far been widely replicated, suggesting a need for larger meta-analysis studies. In the present study, the Psychiatric Genomics Consortium Major Depressive Disorder working group conducted a meta-analysis of methylome-wide association analysis (MWAS) for life-time MD across 18 studies of 24,754 European-ancestry participants (5,443 MD cases) and an East Asian sample (243 cases, 1846 controls). We identified fifteen CpG sites associated with lifetime MD with methylome-wide significance (p < 6.42×10-8). Top CpG effect sizes in European ancestries were positively correlated with those from an independent East Asian MWAS (r = 0.482 and p = 0.068 for significant CpG sites, r = 0.261 and p = 0.009 for the top 100 CpG sites). Methylation score (MS) created using the MWAS summary statistics was significantly associated with MD status in an out-of-sample classification analysis (β = 0.122, p = 0.005, AUC = 0.53). MS was also associated with five inflammatory markers, with the strongest association found with Tumor Necrosis Factor Beta (β=-0.154, p=1.5×10-5). Mendelian randomisation (MR) analysis demonstrated that 23 CpG sites were potentially causally associated with MD and six of those were replicated in an independent mQTL dataset (Wald’s ratio test, absolute β ranged from 0.056 to 0.932, p ranged from 7×10-3to 4.58×10-6). CpG sites located in the Major Histocompatibility complex (MHC) region showed the strongest evidence from MR analysis of being associated with MD. Our study provides evidence that variations in DNA methylation are associated with MD, and further evidence supporting involvement of the immune system. Larger sample sizes in diverse ancestries are likely to reveal replicable associations to improve mechanistic inferences with the potential to inform molecular target identification.

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Section: Discussionmentioning

confidence: 88%

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

Shen,

Barbu,

Caramaschi

et al. 2023

Preprint

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“…Many sequence variants at the 2q14 locus have been reported to associate with other phenotypes, such as C-reactive protein levels 25 and white blood cell count (WBC). 26 We tested the 2 pericarditis variants and highly correlated (r 2 > 0.8) variants for associations with 29 phenotypes and performed co-localization analysis for significant associations (P < .00172 = 0.05/29, eTables 9 and 10 in Supplement 1).…”

Section: Resultsmentioning

confidence: 99%

Variants at the Interleukin 1 Gene Locus and Pericarditis

Thorolfsdottir,

Jonsdottir,

Sveinbjornsson

et al. 2024

JAMA Cardiol

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ImportanceRecurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood.ObjectiveTo use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis.Design, Setting, and ParticipantsThis was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023.ExposureGenotype.Main Outcomes and MeasuresPericarditis.ResultsIn this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10−16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10−8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein β (encoded by CEBPB).Conclusions and RelevanceThis study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1–blocking drugs.

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“…The PKHD1 gene has been associated to T2DM ( 53 ), coronary artery disease ( 49 , 74 ), cardiac troponin T levels ( 75 ), and obesity-related traits ( 44 , 57 , 76 ). While the MAST1 gene has not been associated to cardiovascular complications, it has been reported to be linked glycated hemoglobin levels ( 77 ).…”

Section: Resultsmentioning

confidence: 99%

“…Cardiovascular complications in T2DM is associated to PKHD1 (rs62406032), MAST1 (rs1078264), GFY (rs480265), SEPT14 (rs146350220), PCNT (rs6518289, rs2839227, rs2839223) and RILPL2 (rs28434767). Interestingly, these markers have been associated to coronary artery disease, glycated hemoglobin levels, cardiac troponin T levels, and obesity-related traits (44, 49,57,[74][75][76][77].…”

Section: Discussionmentioning

confidence: 99%

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

et al. 2023

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BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina’s Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina’s Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

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Pleiotropic genetic architecture and novel loci for C-reactive protein levels

Cited by 17 publications

References 37 publications

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

A methylome-wide association study of major depression with out-of-sample case-control classification and trans-ancestry comparison

Variants at the Interleukin 1 Gene Locus and Pericarditis

Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses

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