Bidirectional Mendelian randomization study of brain imaging-derived phenotypes unveils causal associations between thalamic nuclei volume and stroke risk

Abstract

Aim: Recent advances in brain-imaging techniques have enabled the identification of brain imaging-derived phenotypes (IDPs), representing physiological brain structure. Observational studies have suggested a correlation between these IDPs and stroke, which is confounded and based on limited samples. To investigate the causal relationship between IDPs and stroke and its subtypes for an in-depth mechanistic comprehension of their interplay, we conducted a bidirectional two-sample Mendelian Randomization (MR) study leveraging the largest-scale genome-wide association studies (GWAS) of IDPs and stroke subtypes.

Methods: We utilized GWAS summary statistics from the BIG40 dataset, which included nearly 3,935 IDPs among 33,224 individuals, and GIGASTROKE, which included three etiological ischemia subtypes, as well as cerebral ischemia, intracerebral hemorrhage stroke, and overall stroke among 73,652 stroke cases and 1,234,808 controls.

Results: In the forward MR analysis, we identified eight significant IDPs influencing the risk of stroke and its subtypes after Bonferroni correction. Notably, the volume of the lateral posterior thalamus in the right hemisphere exhibited a significant negative association with all ischemic stroke (OR = 0.79; 95%CI: 0.74 to 0.84; P = 1.21e-13), all stroke (OR = 0.84; 95%CI: 0.79 to 0.89; P = 2.45e-9), and large vessel stroke (OR = 0.54; 95%CI: 0.43 to 0.69; P = 3.01e-7). Conversely, no significant causal association was observed in the reverse MR analysis.

Conclusion: This study enhances our understanding of causality between IDPs and stroke by pinpointing specific causal associations. These findings provide valuable insights into the etiology of stroke, offering potential strategies for predicting and intervening in stroke risk at the level of brain imaging.

Keywords

Brain imaging-derived phenotypes / stroke / genetics / causal inference / Mendelian randomization

References

[1] CampbellBCV.Stroke.Lancet2020;396:129-42

[2] GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021;20:795-820. PMCID:PMC8443449

[3] GasullT.Molecular mechanisms and pathophysiology of acute stroke: emphasis on biomarkers in the different stroke subtypes.Int J Mol Sci2022;23:9476 PMCID:PMC9409332

[4] CampbellBCV,MacleodMR.Ischaemic stroke.Nat Rev Dis Primers2019;5:70

[5] GongW,SmithSM.Phenotype discovery from population brain imaging.Med Image Anal2021;71:102050 PMCID:PMC8850869

[6] MillerKL,BangerterNK.Multimodal population brain imaging in the UK Biobank prospective epidemiological study.Nat Neurosci2016;19:1523-36 PMCID:PMC5086094

[7] KaffashianS,ZhuYC,DebetteS.Differential effect of white-matter lesions and covert brain infarcts on the risk of ischemic stroke and intracerebral hemorrhage.Stroke2016;47:1923-5

[8] LiuJ,QinW.Cortical structural changes after subcortical stroke: patterns and correlates.Hum Brain Mapp2023;44:727-43 PMCID:PMC9842916

[9] ZhangQ,WuS.Diffuse tract damage correlates with global cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: a tract-based spatial statistics study.J Comput Assist Tomogr2021;45:285-93

[10] SiemonsenS,HolstB.Quantitative t2 values predict time from symptom onset in acute stroke patients.Stroke2009;40:1612-6

[11] WangZ,LiuC.A study of neurite orientation dispersion and density imaging in ischemic stroke.Magn Reson Imaging2019;57:28-33

[12] BurgessS,ThompsonSG.Combining information on multiple instrumental variables in Mendelian randomization: comparison of allele score and summarized data methods.Stat Med2016;35:1880-906 PMCID:PMC4832315

[13] JiaY,SunL.Mendelian randomization analysis implicates bidirectional associations between brain imaging-derived phenotypes and ischemic stroke.Cereb Cortex2023;33:10848-57

[14] YuK,GuoJ.Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study.BMC Med2023;21:271 PMCID:PMC10369749

[15] MishraA,HachiyaT.COMPASS ConsortiumINVENT ConsortiumDutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study GroupEstonian BiobankPRECISE4Q ConsortiumFinnGen ConsortiumNINDS Stroke Genetics Network (SiGN)MEGASTROKE ConsortiumSIREN ConsortiumChina Kadoorie Biobank Collaborative GroupVA Million Veteran ProgramInternational Stroke Genetics Consortium (ISGC)Biobank JapanCHARGE ConsortiumGIGASTROKE ConsortiumStroke genetics informs drug discovery and risk prediction across ancestries.Nature2022;611:115-23 PMCID:PMC9524349

[16] YangX,LinS.Brain imaging-derived phenotypes and stroke: a bidirectional Mendelian randomization study unveils causal links between thalamic nuclei volume and stroke risk in the European population.medRxiv2025;2025.03.22.25324441

[17] SmithSM,ChenW.An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank.Nat Neurosci2021;24:737-45 PMCID:PMC7610742

[18] YangJ,GoddardME.GCTA: a tool for genome-wide complex trait analysis.Am J Hum Genet2011;88:76-82 PMCID:PMC3014363

[19] HartwigFP,BowdenJ.Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption.Int J Epidemiol2017;46:1985-98 PMCID:PMC5837715

[20] BowdenJ,BurgessS.Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression.Int J Epidemiol2015;44:512-25 PMCID:PMC4469799

[21] CasanovaC,MolotchnikoffS.Pulvina-lateralis posterior nucleus complex of mammals and the visual function.J Physiol1991;85:44-57

[22] MotlesE,GonzálezM.Role of the pulvinar lateralis posterior complex on the rotation response. Relation with other cerebral structures. Pharmacological systems involved in this behavior.Acta Physiol Pharmacol Latinoam1985;35:237-49

[23] CarreraE,BogousslavskyJ.Anteromedian, central, and posterolateral infarcts of the thalamus: three variant types.Stroke2004;35:2826-31

[24] ArboixA,García-ErolesL.Clinical study of 99 patients with pure sensory stroke.J Neurol2005;252:156-62

[25] ShibataH.Organization of anterior cingulate and frontal cortical projections to the anterior and laterodorsal thalamic nuclei in the rat.Brain Res2005;1059:93-103

[26] BezdudnayaT.Laterodorsal nucleus of the thalamus: a processor of somatosensory inputs.J Comp Neurol2008;507:1979-89 PMCID:PMC2800129

[27] YeterianEH.Corticothalamic connections of paralimbic regions in the rhesus monkey.J Comp Neurol1988;269:130-46

[28] BaleydierC.The duality of the cingulate gyrus in monkey. Neuroanatomical study and functional hypothesis.Brain1980;103:525-54

[29] LuppiM,DiCristoforo A.c-Fos expression in the limbic thalamus following thermoregulatory and wake-sleep changes in the rat.Exp Brain Res2019;237:1397-407

[30] ShibataH.Thalamocortical projections of the anteroventral thalamic nucleus in the rabbit.J Comp Neurol2015;523:726-41

[31] FornoG,ContadorJ.Thalamic nuclei changes in early and late onset Alzheimer’s disease.Curr Res Neurobiol2023;4:100084

[32] VertesRP,RojasAKP.Structural and functional organization of the midline and intralaminar nuclei of the thalamus.Front Behav Neurosci2022;16:964644 PMCID:PMC9445584

[33] XuJ,PokB.Thalamic stimulation improves postictal cortical arousal and behavior.J Neurosci2020;40:7343-54

[34] SakayoriN,SugawaraM.Motor skills mediated through cerebellothalamic tracts projecting to the central lateral nucleus.Mol Brain2019;12:13 PMCID:PMC6368787

[35] ConradJ,RuehlRM.White matter volume loss drives cortical reshaping after thalamic infarcts.Neuroimage Clin2022;33:102953 PMCID:PMC8844789

[36] KimYS,NohKC.Distal versus proximal middle cerebral artery occlusion: different mechanisms.Cerebrovasc Dis2019;47:238-44

[37] IlvesN,IlvesN.Ipsilesional volume loss of basal ganglia and thalamus is associated with poor hand function after ischemic perinatal stroke.BMC Neurol2022;22:23 PMCID:PMC8753896

[38] GengJ,RamirezJ.Secondary thalamic atrophy related to brain infarction may contribute to post-stroke cognitive impairment.J Stroke Cerebrovasc Dis2023;32:106895

[39] EgorovaN,HachinskiV.Predicted brain age after stroke.Front Aging Neurosci2019;11:348 PMCID:PMC6914736

[40] LiewSL,SchweighoferN.ENIGMA Stroke Recovery Working GroupSmaller spared subcortical nuclei are associated with worse post-stroke sensorimotor outcomes in 28 cohorts worldwide.Brain Commun2021;3:fcab254