1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.
Ida Elken SonderbyDennis van der MeerClara A MoreauTobias KaufmannG Bragi WaltersMaria EllegaardAbdel AbdellaouiDavid AmesKatrin AmuntsMicael AnderssonNicola J ArmstrongManon BernardNicholas B BlackburnJohn E BlangeroDorret I BoomsmaHenry BrodatyRachel M BrouwerRobin BülowRune BøenWiepke CahnVince D CalhounSvenja CaspersChristopher R K ChingSven CichonSimone CiufoliniBenedicto Crespo-FacorroJoanne E CurranAnders M DaleShareefa DalviePaola DazzanEco J C N de GeusGreig I de ZubicaraySonja M C de ZwarteSylvane DesrivieresJoanne L DohertyGary DonohoeBogdan DraganskiStefan EhrlichElse EisingThomas EspesethKim FejginSimon E FisherTormod FladbyOleksandr FreiVincent FrouinMasaki FukunagaThomas GareauTian GeDavid C GlahnHans Jörgen GrabeNynke A GroenewoldÓmar GústafssonJan HaavikAsta K HabergJeremy HallRyota HashimotoJayne Y Hehir-KwaDerrek P HibarManon H J HillegersPer HoffmannLaurena HolleranAvram J HomesGeorg HomuthJouke- Jan HottengaHilleke E Hulshoff PolKyung Sue HongNeda JahanshadChristiane JockwitzStefan E JohanssonErik G JönssonNiklas R JørgensenMasataka KikuchiEmma E M KnowlesKuldeep KumarStephanie Le HellardCostin LeuDavid E J LindenJingyu LiuArvid LundervoldAstri Johansen LundervoldAnne Manuela MaillardNicholas G MartinSandra Martin-BrevetKaren A MatherSamuel R MathiasKatie L McmahonAllan F McRaeSarah E MedlandAndreas Meyer-LindenbergTorgeir MobergetClaudia ModenatoJennifer Monereo SánchezDerek W MorrisThomas W MühleisenRobin M MurrayJacob NielsenJan E NordvikLars NybergLoes M Olde LoohuisRoel A OphoffMichael J OwenTomáš PausZdenka PausovaJuan M PeraltaGilbert Bruce PikeCarlos PrietoErin Burke QuinlanCéline S ReinboldTiago Reis MarquesJames J H RuckerPerminder Singh SachdevSigrid B SandoPeter R SchofieldAndrew J SchorkGunter SchumannJean ShinElena ShumskayaAna Isabel SilvaSanjay M SisodiyaVidar M SteenDan J SteinLachlan T StrikeIkuo K SuzukiChristian K TamnesAlexander TeumerAnbupalam ThalamuthuDiana Tordesillas-GutiérrezAnne UhlmannMagnus O UlfarssonDennis van 't EntMarianne B M van den BreePierre VanderhaeghenEvangelos VassosWei WenKatharina WittfeldMargaret J WrightIngrid AgartzSrdjan DjurovicLars Tjelta WestlyeHreinn StefánssonKári StefánssonSebastien JacquemontPaul M ThompsonOle Andreas Andreassennull nullPublished in: Translational psychiatry (2021)
Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.
Keyphrases
- copy number
- mitochondrial dna
- intellectual disability
- genome wide
- white matter
- resting state
- magnetic resonance imaging
- dna methylation
- functional connectivity
- cerebral ischemia
- autism spectrum disorder
- minimally invasive
- endothelial cells
- cross sectional
- computed tomography
- subarachnoid hemorrhage
- brain injury
- working memory
- depressive symptoms
- multiple sclerosis
- high resolution
- magnetic resonance
- optic nerve
- mass spectrometry
- image quality
- cerebral blood flow