Cerebral small vessel disease genomics and its implications across the lifespan.
Muralidharan SargurupremrajHideaki SuzukiXueqiu JianChloe SarnowskiTavia E EvansJoshua C BisGudny EiriksdottirSaori SakaueNatalie TerzikhanMohamad HabesWei ZhaoNicola J ArmstrongEdith HoferLisa R YanekSaskia P HagenaarsRajan B KumarErik B van den AkkerRebekah E McWhirterStella TrompetAniket MishraYasaman SabaClaudia L SatizabalGregory BeaudetLaurent PetitAmi TsuchidaLaure ZagoSabrina SchillingSigurdur SigurdssonRebecca F GottesmanCora E LewisNeelum T AggarwalOscar L LopezJennifer A SmithMaria C Valdés HernándezJeroen van der GrondMargaret J WrightMaria J KnolMarcus DörrRussell J ThomsonConstance BordesQuentin Le GrandMarie-Gabrielle DuperronAlbert Vernon SmithDavid S KnopmanPamela J SchreinerDenis A EvansJerome I RotterAlexa S BeiserSusana Muñoz ManiegaMarian BeekmanJulian N TrollorDavid J StottMeike W VernooijKatharina WittfeldWiro J NiessenAicha SoumaréEric BoerwinkleStephen SidneyStephen T TurnerGail DaviesAnbupalam ThalamuthuLinus VölkerMark A van BuchemR Nick BryanJosée DupuisMark E BastinDavid AmesAlexander TeumerPhillippe AmouyelJohn B KwokRobin BülowIan J DearyPeter R SchofieldHenry BrodatyJiyang JiangYasuharu TabaraKazuya SetohSusumu MiyamotoKazumichi YoshidaManabu NagataYoichiro KamataniFumihiko MatsudaBruce M PsatyDavid A BennettPhilip Lawrence De JagerThomas H MosleyPerminder Singh SachdevReinhold SchmidtHelen R WarrenEvangelos EvangelouDavid-Alexandre Trégouëtnull nullnull nullMohammad Arfan IkramWei WenCharles DeCarliVelandai K SrikanthJohan Wouter JukemaPieternella Eline SlagboomSharon L R KardiaYukinori OkadaBernard MazoyerJoanna Marguerite WardlawPaul A NyquistKaren A MatherHans Jörgen GrabeHelena SchmidtCornelia M Van DuijnVilmundur G GudnasonWilliam T LongstrethLenore J LaunerMark LathropSudha SeshadriChristophe TzourioHieab H H AdamsPaul M MatthewsMyriam FornageStephanie DebettePublished in: Nature communications (2020)
White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
Keyphrases
- genome wide
- white matter
- blood pressure
- copy number
- dna methylation
- multiple sclerosis
- cerebral ischemia
- hypertensive patients
- deep learning
- subarachnoid hemorrhage
- heart rate
- poor prognosis
- risk factors
- gene expression
- mild cognitive impairment
- high resolution
- middle aged
- skeletal muscle
- cognitive decline
- metabolic syndrome
- adverse drug
- long non coding rna
- transcription factor
- photodynamic therapy
- blood glucose
- drug induced
- mass spectrometry
- fluorescence imaging