Co-regulatory networks of human serum proteins link genetics to disease

Emilsson, Valur; Ilkov, Marjan; Lamb, John; Finkel, Nancy; Gudmundsson, Elias F.; Pitts, Rebecca; Hoover, Heather; Guðmundsdóttir, Valborg; Horman, Shane R.; Aspelund, Thor; Shu, Le; Трифонов, Владимир; Sigurðsson, Sigurður; Manolescu, Andrei; Zhu, Jun; Ólafsson, Ö; Jakobsdóttir, Jóhanna; Lesley, Scott A.; To, Jeremy; Jia, Zhiying; Harris, Tamara B.; Launer, Lenore J.; Zhang, Bin; Eiríksdóttir, Guðný; Yang, Xia; Orth, Anthony P.; Jennings, Lori L.; Gudnason, Vilmundur

doi:10.1126/science.aaq1327

Cited by 445 publications

(707 citation statements)

References 69 publications

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“…Genome-wide association (GWA) analyses could identify these genes or variants. There are several GWA studies of FA (Elliott et al, 2017;Lopez et al, 2012;Sprooten et al, 2013Sprooten et al, , 2014 and inflammatory measures (Ahola-Olli et al, 2017;Emilsson et al, 2018;Folkersen et al, 2017;Kim et al, 2012;Larsen et al, 2013;Li et al, 2016;Sun et al, 2018). While these analyses successfully identify loci underlying individual variation in these traits, they fail to identify variants common to both.…”

Section: Discussionmentioning

confidence: 99%

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation

Rodrigue

Knowles

Mollon

et al. 2019

Human Brain Mapping

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White matter microstructure is affected by immune system activity via the actions of circulating pro‐inflammatory cytokines. Although white matter microstructure and inflammatory measures are significantly heritable, it is unclear if overlapping genetic factors influence these traits in humans. We conducted genetic correlation analyses of these traits using randomly ascertained extended pedigrees from the Genetics of Brain Structure and Function Study (N = 1862, 59% females, ages 18–97 years; 42 ± 15.7). White matter microstructure was assessed using fractional anisotropy (FA) calculated from diffusion tensor imaging (DTI). Circulating levels (pg/mL) of pro‐inflammatory cytokines (IL‐6, IL‐8, and TNFα) phenotypically associated with white matter microstructure were quantified from blood serum. All traits were significantly heritable (h2 ranging from 0.41 to 0.66 for DTI measures and from 0.18 to 0.30 for inflammatory markers). Phenotypically, higher levels of circulating inflammatory markers were associated with lower FA values across the brain (r = −.03 to r = −.17). There were significant negative genetic correlations between most DTI measures and IL‐8 and TNFα, although effects for TNFα were no longer significant when covarying for body mass index. Genetic correlations between DTI measures and IL‐6 were not significant. Understanding the genetic correlation between specific inflammatory markers and DTI measures may help researchers focus questions related to inflammatory processes and brain structure.

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Section: Discussionmentioning

confidence: 99%

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation

Rodrigue

Knowles

Mollon

et al. 2019

Human Brain Mapping

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“…Plasma proteins span a dynamic range of up to 12 logs, and many relevant biomarkers are likely low abundant (e.g., cytokines) and not be readily detected by MS‐based strategies [38]. SOMAscan has been successful for biomarker discovery in multiple diseases [35,37,39], including AD. SOMAscan has been well‐validated against other proteomic platforms, including liquid chromatography‐mass spectrometry/mass spectrometry and gold‐standard ELISA measures [39,40].…”

Section: Methodsmentioning

confidence: 99%

The Role of Inflammation after Surgery for Elders (RISE) study: Study design, procedures, and cohort profile

Hshieh

Vasunilashorn

D'Aquila

et al. 2019

Alz & Dem Diag Ass & Dis Mo

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Introduction The Role of Inflammation after Surgery for Elders study correlates novel inflammatory markers measured in blood, cerebrospinal fluid (CSF) assays, and [11C]‐PBR28 positron‐emission tomography imaging. Methods This study involved a prospective cohort design with patients who underwent elective hip and knee arthroplasty under spinal anesthesia. Sixty‐five adults participated with their family members. Inflammatory biomarker assays were measured preoperatively on day 1 and postoperatively at one month. Results On average, participants were 75 years old, and 72% were female. 54% underwent total knee arthroplasty, and 46% underwent total hip arthroplasty. The mean Modified Mini‐Mental State (3MS) Examination score was 89.3; four patients (6%) scored ≤77 points. Plasma assays were completed in 63 (97%) participants, cerebrospinal fluid assays in 61 (94%), and PET imaging in 44 (68%). Discussion This complex study presents an innovative effort to correlate peripheral and central inflammatory biomarkers before and after major surgery in older adults. Strengths include collecting concurrent blood, cerebrospinal fluid, and positron‐emission tomography with detailed clinical characterization of delirium, cognition, and functional status.

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“…We obtained summary statistics data derived from the analysis conducted for histologically confirmed incident breast cancers (ICD‐10: C50, n = 5,510) and prevalent breast cancers reported by participants at the baseline interview ( n = 7,480). We also abstracted pQTL variants from other two genome‐wide pQTL studies ( p < 5 × 10 −8 , LD R 2 < 0.1) to construct new instruments for the risk‐associated proteins. Both studies were conducted in the populations of European descent and the same SOMAscan platform was used to measure blood proteins.…”

Section: Methodsmentioning

confidence: 99%

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk

Shu

Bao

et al. 2019

Intl Journal of Cancer

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A small number of circulating proteins have been reported to be associated with breast cancer risk, with inconsistent results. Herein, we attempted to identify novel protein biomarkers for breast cancer via the integration of genomics and proteomics data. In the Breast Cancer Association Consortium (BCAC), with 122,977 cases and 105,974 controls of European descendants, we evaluated the associations of the genetically predicted concentrations of >1,400 circulating proteins with breast cancer risk. We used data from a large‐scale protein quantitative trait loci (pQTL) analysis as our study instrument. Summary statistics for these pQTL variants related to breast cancer risk were obtained from the BCAC and used to estimate odds ratios (OR) for each protein using the inverse‐variance weighted method. We identified 56 proteins significantly associated with breast cancer risk by instrumental analysis (false discovery rate <0.05). Of these, the concentrations of 32 were influenced by variants close to a breast cancer susceptibility locus (ABO, 9q34.2). Many of these proteins, such as insulin receptor, insulin‐like growth factor receptor 1 and other membrane receptors (OR: 0.82–1.18, p values: 6.96 × 10−4–3.28 × 10−8), are linked to insulin resistance and estrogen receptor signaling pathways. Proteins identified at other loci include those involved in biological processes such as alcohol and lipid metabolism, proteolysis, apoptosis, immune regulation and cell motility and proliferation. Consistent associations were observed for 22 proteins in the UK Biobank data (p < 0.05). The study identifies potential novel biomarkers for breast cancer, but further investigation is needed to replicate our findings.

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Co-regulatory networks of human serum proteins link genetics to disease

Cited by 445 publications

References 69 publications

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation

Evidence for genetic correlation between human cerebral white matter microstructure and inflammation

The Role of Inflammation after Surgery for Elders (RISE) study: Study design, procedures, and cohort profile

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk

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