Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Stroke | Research article

Identification of novel proteins for lacunar stroke by integrating genome-wide association data and human brain proteomes

Authors: Chengcheng Zhang, Fengqin Qin, Xiaojing Li, Xiangdong Du, Tao Li

Published in: BMC Medicine | Issue 1/2022

Login to get access

Abstract

Background

Previous genome-wide association studies (GWAS) have identified numerous risk genes for lacunar stroke, but it is challenging to decipher how they confer risk for the disease. We employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for lacunar stroke.

Methods

We systematically integrated lacunar stroke genome-wide association study (GWAS) (N=7338) with human brain proteomes (N=376) to perform proteome-wide association studies (PWAS), Mendelian randomization (MR), and Bayesian colocalization. We also used an independent human brain proteomic dataset (N=152) to annotate the new genes.

Results

We found that the protein abundance of seven genes (ICA1L, CAND2, ALDH2, MADD, MRVI1, CSPG4, and PTPN11) in the brain was associated with lacunar stroke. These seven genes were mainly expressed on the surface of glutamatergic neurons, GABAergic neurons, and astrocytes. Three genes (ICA1L, CAND2, ALDH2) were causal in lacunar stroke (P < 0.05/proteins identified for PWAS; posterior probability of hypothesis 4 ≥ 75 % for Bayesian colocalization), and they were linked with lacunar stroke in confirmatory PWAS and independent MR. We also found that ICA1L is related to lacunar stroke at the brain transcriptome level.

Conclusions

Our present proteomic findings have identified ICA1L, CAND2, and ALDH2 as compelling genes that may give key hints for future functional research and possible therapeutic targets for lacunar stroke.
Appendix
Available only for authorised users
Literature
1.
2.
Regenhardt RW, Das AS, Lo EH, Caplan LR. Advances in understanding the pathophysiology of lacunar stroke: a review. JAMA Neurol. 2018;75(10):1273–81.PubMedPubMedCentralCrossRef
3.
Tam V, Patel N, Turcotte M, Bossé Y, Paré G, Meyre D. Benefits and limitations of genome-wide association studies. Nat Rev Genet. 2019;20(8):467–84.PubMedCrossRef
4.
Yang C, Farias FHG. Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nat Neurosci. 2021;24(9):1302–12.PubMedPubMedCentralCrossRef
5.
Sharma K, Schmitt S, Bergner CG, Tyanova S, Kannaiyan N, Manrique-Hoyos N, et al. Cell type– and brain region–resolved mouse brain proteome. Nat Neurosci. 2015;18(12):1819–31.PubMedPubMedCentralCrossRef
6.
Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13(4):227–32.PubMedPubMedCentralCrossRef
7.
Rolland DCM, Basrur V, Jeon Y-K, McNeil-Schwalm C, Fermin D, Conlon KP, et al. Functional proteogenomics reveals biomarkers and therapeutic targets in lymphomas. Proc Natl Acad Sci. 2017;114(25):6581–6.PubMedPubMedCentralCrossRef
8.
9.
Asoh S, Ohsawa I, Mori T, Katsura K-I, Hiraide T, Katayama Y, et al. Protection against ischemic brain injury by protein therapeutics. Proc Natl Acad Sci. 2002;99(26):17107–12.PubMedPubMedCentralCrossRef
10.
11.
Imamura A, Morimoto Y, Ono S, Kurotaki N, Kanegae S, Yamamoto N, et al. Genetic and environmental factors of schizophrenia and autism spectrum disorder: insights from twin studies. J Neural Transm (Vienna). 2020;127(11):1501–15.CrossRef
12.
Wingo TS, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM, et al. Brain proteome-wide association study implicates novel proteins in depression pathogenesis. Nat Neurosci. 2021;24(6):810–7.PubMedPubMedCentralCrossRef
13.
Traylor M, Malik R, Nalls MA, Cotlarciuc I, Radmanesh F, Thorleifsson G, et al. Genetic variation at 16q24. 2 is associated with small vessel stroke. Ann Neurol. 2017;81(3):383–94.PubMedPubMedCentralCrossRef
14.
Traylor M, Persyn E, Tomppo L, Klasson S, Abedi V, Bakker MK, et al. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol. 2021;20(5):351–61.PubMedPubMedCentralCrossRef
15.
Wingo AP, Dammer EB, Breen MS, Logsdon BA, Duong DM, Troncosco JC, et al. Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age. Nat Commun. 2019;10(1):1619.PubMedPubMedCentralCrossRef
16.
17.
Ou Y-N, Yang Y-X, Deng Y-T, Zhang C, Hu H, Wu B-S, et al. Identification of novel drug targets for Alzheimer’s disease by integrating genetics and proteomes from brain and blood. Mol Psychiatry. 2021;26:6065–73.PubMedCrossRef
18.
Liu J, Li X, Luo X-J. Proteome-wide association study provides insights into the genetic component of protein abundance in psychiatric disorders. Biol Psychiatr. 2021;90(11):781-9.
19.
Wang M, Beckmann ND, Roussos P, Wang E, Zhou X, Wang Q, et al. The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer’s disease. Sci Data. 2018;5(1):1–16.CrossRef
20.
De Jager PL, Ma Y, McCabe C, Xu J, Vardarajan BN, Felsky D, et al. A multi-omic atlas of the human frontal cortex for aging and Alzheimer’s disease research. Sci Data. 2018;5:180142.PubMedPubMedCentralCrossRef
21.
Wingo AP, Liu Y, Gerasimov ES, Gockley J, Logsdon BA, Duong DM, et al. Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer’s disease pathogenesis. Nat Genet. 2021;53(2):143–6.PubMedPubMedCentralCrossRef
22.
Beach TG, Adler CH, Sue LI, Serrano G, Shill HA, Walker DG, et al. Arizona study of aging and neurodegenerative disorders and brain and body donation program. Neuropathology. 2015;35(4):354–89.PubMedPubMedCentralCrossRef
23.
Fromer M, Roussos P, Sieberts SK, Johnson JS, Kavanagh DH, Perumal TM, et al. Gene expression elucidates functional impact of polygenic risk for schizophrenia. Nat Neurosci. 2016;19(11):1442–53.PubMedPubMedCentralCrossRef
24.
Li M, Huang L, Grigoroiu-Serbanescu M, Bergen SE, Landén M, Hultman CM, et al. Convergent lines of evidence support LRP8 as a susceptibility gene for psychosis. Mol Neurobiol. 2016;53(10):6608–19.PubMedCrossRef
25.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75.PubMedPubMedCentralCrossRef
26.
Gusev A, Ko A, Shi H, Bhatia G, Chung W, Penninx BWJH, et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet. 2016;48(3):245–52.PubMedPubMedCentralCrossRef
27.
Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet. 2014;23(R1):R89–98.PubMedPubMedCentralCrossRef
28.
Rasooly D, Patel CJ. Conducting a reproducible Mendelian randomization analysis using the R analytic statistical environment. Curr Protoc Hum Genet. 2019;101(1):e82.PubMedPubMedCentral
29.
Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018;7:e34408.PubMedPubMedCentralCrossRef
30.
Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 2014;10(5):e1004383.PubMedPubMedCentralCrossRef
31.
Su X, Li W, Lv L, Li X, Yang J, Luo X-J, et al. Transcriptome-wide association study provides insights into the genetic component of gene expression in anxiety. Front Genet. 2021;12:740134.PubMedPubMedCentralCrossRef
32.
33.
Marbach D, Costello JC, Küffner R, Vega NM, Prill RJ, Camacho DM, et al. Wisdom of crowds for robust gene network inference. Nat Methods. 2012;9(8):796–804.PubMedPubMedCentralCrossRef
34.
Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, et al. Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018;50(4):524–37.PubMedPubMedCentralCrossRef
35.
Knol MJ, Lu D, Traylor M, Adams HHH, Romero JRJ, Smith AV, et al. Association of common genetic variants with brain microbleeds: a genome-wide association study. Neurology. 2020;95(24):e3331–43.PubMedPubMedCentralCrossRef
36.
Nagel M, Jansen PR, Stringer S. Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. Nat Genet. 2018;50(7):920–7.PubMedCrossRef
37.
Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, et al. Meta-analysis of genome-wide association studies for height and body mass index in ∼700000 individuals of European ancestry. Hum Mol Genet. 2018;27(20):3641–9.PubMedPubMedCentralCrossRef
38.
Pulit SL, Stoneman C, Morris AP, Wood AR, Glastonbury CA, Tyrrell J, et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum Mol Genet. 2019;28(1):166–74.PubMedCrossRef
39.
Liu M, Xu P, Guan Z, Qian X, Dockery P, Fitzgerald U, et al. Ulk4 deficiency leads to hypomyelination in mice. Glia. 2018;66(1):175–90.PubMedCrossRef
40.
Akiyama K, Liang YQ, Isono M, Kato N. Investigation of functional genes at homologous loci identified based on genome-wide association studies of blood lipids via high-fat diet intervention in rats using an in vivo approach. J Atheroscler Thromb. 2015;22(5):455–80.PubMedCrossRef
41.
Centeno C, Repici M, Chatton JY, Riederer BM, Bonny C, Nicod P, et al. Role of the JNK pathway in NMDA-mediated excitotoxicity of cortical neurons. Cell Death Differ. 2007;14(2):240–53.PubMedCrossRef
42.
Belov Kirdajova D, Kriska J, Tureckova J, Anderova M. Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front Cell Neurosci. 2020;14:51.PubMedPubMedCentralCrossRef
43.
Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009;41(1):47–55.PubMedCrossRef
44.
Wang XB, Han YD, Cui NH, Gao JJ, Yang J, Huang ZL, et al. Associations of lipid levels susceptibility loci with coronary artery disease in Chinese population. Lipids Health Dis. 2015;14:80.PubMedPubMedCentralCrossRef
45.
Koskimäki J, Zhang D, Li Y, Saadat L, Moore T, Lightle R, et al. Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations. Acta Neuropathol Commun. 2019;7(1):132.PubMedPubMedCentralCrossRef
46.
Wang Q, Meng L, Wang Z. Combined cerebral microbleeds with lacunar infarctions in familial cerebral cavernous malformations. JAMA Neurol. 2019;76(9):1117–8.CrossRef
47.
Johnson AD, Yanek LR, Chen MH, Faraday N, Larson MG, Tofler G, et al. Genome-wide meta-analyses identifies seven loci associated with platelet aggregation in response to agonists. Nat Genet. 2010;42(7):608–13.PubMedPubMedCentralCrossRef
48.
Tsai SH, Hsu LA, Tsai HY, Yeh YH, Lu CY, Chen PC, et al. Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells. FASEB J. 2020;34(7):9498–511.PubMedCrossRef
49.
Kessler T, Schunkert H, von Hundelshausen P. Novel approaches to fine-tune therapeutic targeting of platelets in atherosclerosis: a critical appraisal. Thromb Haemost. 2020;120(11):1492–504.PubMedCrossRef
50.
Rouhl RP, Damoiseaux JG, Lodder J, Theunissen RO, Knottnerus IL, Staals J, et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging. 2012;33(8):1800–6.PubMedCrossRef
51.
Acampa M, Lazzerini PE, Manfredi C, Guideri F, Tassi R, Domenichelli C, et al. Non-stenosing carotid atherosclerosis and arterial stiffness in embolic stroke of undetermined source. Front Neurol. 2020;11:725.PubMedPubMedCentralCrossRef
52.
Nishiyama A, Dahlin KJ, Prince JT, Johnstone SR, Stallcup WB. The primary structure of NG2, a novel membrane-spanning proteoglycan. J Cell Biol. 1991;114(2):359–71.PubMedCrossRef
53.
Fung K, Ramírez J, Warren HR, Aung N, Lee AM, Tzanis E, et al. Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants. Sci Rep. 2019;9(1):9143.PubMedPubMedCentralCrossRef
54.
Santoro C, Giugliano T, Kraemer M, Torella A, Schwitalla JC, Cirillo M, et al. Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1. PLoS One. 2018;13(7):e0200446.PubMedPubMedCentralCrossRef
55.
Rudzik R, Dziedziejko V, Rać ME, Sawczuk M, Maciejewska-Skrendo A, Safranow K, et al. Polymorphisms in GP6, PEAR1A, MRVI1, PIK3CG, JMJD1C, and SHH genes in patients with unstable angina. Int J Environ Res Public Health. 2020;17(20):7506.PubMedCentralCrossRef
56.
Liu KW, Feng H, Bachoo R, Kazlauskas A, Smith EM, Symes K, et al. SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. J Clin Investig. 2011;121(3):905–17.PubMedPubMedCentralCrossRef
57.
Sang Y, Hou Y, Cheng R, Zheng L, Alvarez AA, Hu B, et al. Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2-mediated signaling. Neuro-Oncology. 2019;21(11):1423–35.PubMedPubMedCentralCrossRef
58.
Roccograndi L, Binder ZA, Zhang L, Aceto N, Zhang Z, Bentires-Alj M, et al. SHP2 regulates proliferation and tumorigenicity of glioma stem cells. J Neuro-Oncol. 2017;135(3):487–96.CrossRef
59.
Yang Z, Li Y, Yin F, Chan RJ. Activating PTPN11 mutants promote hematopoietic progenitor cell-cycle progression and survival. Exp Hematol. 2008;36(10):1285–96.PubMedPubMedCentralCrossRef
60.
61.
Gusev A, Mancuso N, Won H, Kousi M, Finucane HK, Reshef Y, et al. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. Nat Genet. 2018;50(4):538–48.PubMedPubMedCentralCrossRef
62.
Kaiser J, Maibach M, Salpeter I, Hagenbuch N, de Souza VBC, Robinson MD, et al. The spinal transcriptome after cortical stroke: in search of molecular factors regulating spontaneous recovery in the spinal cord. J Neurosci. 2019;39(24):4714–26.PubMedPubMedCentralCrossRef
63.
Battle A, Khan Z, Wang SH, et al. Genomic variation. Impact of regulatory variation from RNA to protein. Science. 2015;347(6222):664-7.
64.
Albert FW, Kruglyak L. The role of regulatory variation in complex traits and disease. Nat Rev Genet. 2015;16(4):197–212.PubMedCrossRef
65.
Carvalho-Silva D, Pierleoni A, Pignatelli M, Ong C, Fumis L, Karamanis N, et al. Open Targets Platform: new developments and updates two years on. Nucleic Acids Res. 2019;47(D1):D1056–d1065.PubMedCrossRef
66.
Kwan A, Wei J, Dowling NM, Power MC, Nadareishvili Z. Cognitive impairment after lacunar stroke and the risk of recurrent stroke and death. Cerebrovasc Dis. 2021;50(4):383–9.PubMedCrossRef
67.
Clark SJ, Lee HJ, Smallwood SA, Kelsey G, Reik W. Single-cell epigenomics: powerful new methods for understanding gene regulation and cell identity. Genome Biol. 2016;17:72.PubMedPubMedCentralCrossRef
68.
Metadata
Title
Identification of novel proteins for lacunar stroke by integrating genome-wide association data and human brain proteomes
Authors
Chengcheng Zhang
Fengqin Qin
Xiaojing Li
Xiangdong Du
Tao Li
Publication date
01-12-2022
Publisher
BioMed Central
Keyword
Stroke
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02408-y

Other articles of this Issue 1/2022

BMC Medicine 1/2022 Go to the issue

Research article

Is glycaemic control associated with dietary patterns independent of weight change in people newly diagnosed with type 2 diabetes? Prospective analysis of the Early-ACTivity-In-Diabetes trial

Editorial

Turning the tide towards cardiovascular prevention

Research article

Combined impact of lipidomic and genetic aberrations on clinical outcomes in metastatic castration-resistant prostate cancer

Research article

Identification of risk factors for incident cervical insufficiency in nulliparous and parous women: a population-based case-control study

Research article

Tumor PKCδ instigates immune exclusion in EGFR-mutated non–small cell lung cancer

Research article

Genomic correlation, shared loci, and causal relationship between obesity and polycystic ovary syndrome: a large-scale genome-wide cross-trait analysis