1. Science—重磅！！研究揭示了人类大脑皮层各区域表面面积和厚度的遗传学基础

Abstract

The cerebral cortex underlies our complexcognitive capabilities, yet little is known about the specific genetic locithat influence human cortical structure. To identify genetic variants thataffect cortical structure, we conducted a genome-wide association meta-analysisof brain magnetic resonance imaging data from 51,665 individuals. We analyzedthe surface area and average thickness of the whole cortex and 34 regions withknown functional specializations. We identified 199 significant loci and foundsignificant enrichment for loci influencing total surface area withinregulatory elements that are active during prenatal cortical development,supporting the radial unit hypothesis. Loci that affect regional surface areacluster near genes in Wnt signaling pathways, which influence progenitorexpansion and areal identity. Variation in cortical structure is geneticallycorrelated with cognitive function, Parkinson's disease, insomnia, depression,neuroticism, and attention deficit hyperactivity disorder.

参考文献：The genetic architecture of the human cerebralcortex. Science. 2020 Mar 20;367(6484):eaay6690.

 2. Science—哈佛科学家开发Perturb-Seq技术大规模研究自闭症谱系病和神经发育迟滞相关风险基因的生物学效应

Abstract

The number of disease risk genes and lociidentified through human genetic studies far outstrips the capacity tosystematically study their functions. We applied a scalable genetic screeningapproach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrumdisorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes.Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes inpools, within the developing mouse brain in utero, followed by single-cellRNA-sequencing of perturbed cells in the postnatal brain. We identified celltype-specific and evolutionarily conserved gene modules from both neuronal andglial cell classes. Recurrent gene modules and cell types are affected acrossthis cohort of perturbations, representing key cellular effects across sets ofASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diversemutations affect cell types and states in the developing organism.

参考文献：In vivo Perturb-Seq reveals neuronal and glialabnormalities associated with autism risk genes. Science. 2020 Nov27;370(6520):eaaz6063.

 3. Nature genetics—GWAS研究揭示颅内动脉瘤的遗传风险位点：11个新遗传位点+与吸烟/高血压遗传风险重叠

Abstract

Rupture of an intracranial aneurysm leads tosubarachnoid hemorrhage, a severe type of stroke. To discover new risk loci andthe genetic architecture of intracranial aneurysms, we performed a cross-ancestry,genome-wide association study in 10,754 cases and 306,882 controls of Europeanand East Asian ancestry. We discovered 17 risk loci, 11 of which are new. Wereveal a polygenic architecture and explain over half of the diseaseheritability. We show a high genetic correlation between ruptured andunruptured intracranial aneurysms. We also find a suggestive role forendothelial cells by using gene mapping and heritability enrichment.Drug-target enrichment shows pleiotropy between intracranial aneurysms andantiepileptic and sex hormone drugs, providing insights into intracranialaneurysm pathophysiology. Finally, genetic risks for smoking and high bloodpressure, the two main clinical risk factors, play important roles inintracranial aneurysm risk, and drive most of the genetic correlation betweenintracranial aneurysms and other cerebrovascular traits.

参考文献：Genome-wide association study of intracranialaneurysms identifies 17 risk loci and genetic overlap with clinical riskfactors. Nat Genet. 2020 Dec;52(12):1303-1313.

4. Nature genetics—重磅！！科学家发现8个可能引起脑瘫的风险基因：神经突生成异常是关键！！

Abstract

In addition to commonly associatedenvironmental factors, genomic factors may cause cerebral palsy. We performedwhole-exome sequencing of 250 parent-offspring trios, and observed enrichmentof damaging de novo mutations in cerebral palsy cases. Eight genes had multipledamaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-widesignificance. We identified two novel monogenic etiologies, FBXO31 and RHOB,and showed that the RHOB mutation enhances active-state Rho effector bindingwhile the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsyrisk genes overlapped with neurodevelopmental disorder genes. Network analysesidentified enrichment of Rho GTPase, extracellular matrix, focal adhesion andcytoskeleton pathways. Cerebral palsy risk genes in enriched pathways wereshown to regulate neuromotor function in a Drosophila reverse genetics screen.We estimate that 14% of cases could be attributed to an excess of damaging denovo or recessive variants. These findings provide evidence for geneticallymediated dysregulation of early neuronal connectivity in cerebral palsy.

参考文献：Mutations disrupting neuritogenesis genesconfer risk for cerebral palsy. Nat Genet. 2020 Oct;52(10):1046-1056.

5. Nature genetics—重磅突破！！SORD突变是引起隐性遗传性周围神经病的最常见遗传变异

Abstract

Here we report biallelic mutations in thesorbitol dehydrogenase gene (SORD) as the most frequent recessive form ofhereditary neuropathy. We identified 45 individuals from 38 families acrossmultiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27)variant in SORD, in either a homozygous or compound heterozygous state. SORD isan enzyme that converts sorbitol into fructose in the two-step polyol pathwaypreviously implicated in diabetic neuropathy. In patient-derived fibroblasts,we found a complete loss of SORD protein and increased intracellular sorbitol.Furthermore, the serum fasting sorbitol levels in patients were dramaticallyincreased. In Drosophila, loss of SORD orthologs caused synaptic degenerationand progressive motor impairment. Reducing the polyol influx by treatment withaldose reductase inhibitors normalized intracellular sorbitol levels inpatient-derived fibroblasts and in Drosophila, and also dramaticallyameliorated motor and eye phenotypes. Together, these findings establish anovel and potentially treatable cause of neuropathy and may contribute to abetter understanding of the pathophysiology of diabetes.

参考文献：Biallelic mutations in SORD cause a common andpotentially treatable hereditary neuropathy with implications for diabetes. NatGenet. 2020 May;52(5):473-481.

 6. Lancet Neurol—LRRK2位点变异和PSP患者的生存率相关

Abstract

Background: The genetic basis of variation inthe progression of primary tauopathies has not been determined. We aimed toidentify genetic determinants of survival in progressive supranuclear palsy(PSP).

Methods: In stage one of this two stagegenome-wide association study (GWAS), we included individuals with PSP,diagnosed according to pathological and clinical criteria, from two separatecohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic(Jacksonville, FL, USA) and in Munich (Germany), and the University CollegeLondon PSP cohort, from brain banks and the PROSPECT study, a UK-widelongitudinal study of patients with atypical parkinsonian syndromes.Individuals were included if they had clinical data available on sex, age atmotor symptom onset, disease duration (from motor symptom onset to death or tothe date of censoring, Dec 1, 2019, if individuals were alive), and PSPphenotype (with reference to the 2017 Movement Disorder Society criteria).Genotype data were used to do a survival GWAS using a Cox proportional hazardsmodel. In stage two, data from additional individuals from the Mayo Clinicbrain bank, which were obtained after the 2011 PSP GWAS, were used for a pooledanalysis. We assessed the expression quantitative trait loci (eQTL) profile ofvariants that passed genome-wide significance in our GWAS using the FunctionalMapping and Annotation of GWAS platform, and did colocalisation analyses usingthe eQTLGen and PsychENCODE datasets.

Findings: Data were collected and analysed betweenAug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of whiteEuropean ancestry with PSP in stage one. We found a genome-wide significantassociation with survival at chromosome 12 (lead single nucleotide polymorphismrs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 wasassociated with survival in the individuals added in stage two (n=238; p=0·049,1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 ×10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 isassociated with increased expression of LRRK2 and two long intergenicnon-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Althoughwe did not detect a colocalisation signal for LRRK2, analysis of the PSPsurvival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed aposterior probability of hypothesis 4 of 0·77, suggesting colocalisation due toa single shared causal variant.

Interpretation: Genetic variation at the LRRK2locus was associated with survival in PSP. The mechanism of this associationmight be through a lncRNA-regulated effect on LRRK2 expression becauseLINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 hasbeen associated with sporadic and familial forms of Parkinson's disease, andour finding suggests a genetic overlap with PSP. Further functional studieswill be important to assess the potential of LRRK2 modulation as adisease-modifying therapy for PSP and related tauopathies.

参考文献：Genetic determinants of survival inprogressive supranuclear palsy: a genome-wide association study. Lancet Neurol.2020 Dec 17;S1474-4422(20)30394-X.

 7. Cell—迄今为止最大的自闭症全外显子测序揭示了102个风险基因，大多与大脑发育和功能紧密相关

Abstract

We present the largest exome sequencing studyof autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986with ASD). Using an enhanced analytical framework to integrate de novo andcase-control rare variation, we identify 102 risk genes at a false discoveryrate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptivede novo variants in individuals ascertained to have severe neurodevelopmentaldelay, whereas 53 show higher frequencies in individuals ascertained to haveASD; comparing ASD cases with mutations in these groups reveals phenotypicdifferences. Expressed early in brain development, most risk genes have rolesin regulation of gene expression or neuronal communication (i.e., mutationseffect neurodevelopmental and neurophysiological changes), and 13 fall withinloci recurrently hit by copy number variants. In cells from the human cortex,expression of risk genes is enriched in excitatory and inhibitory neuronallineages, consistent with multiple paths to an excitatory-inhibitory imbalanceunderlying ASD.

参考文献：Large-Scale Exome Sequencing Study ImplicatesBoth Developmental and Functional Changes in the Neurobiology of Autism. Cell. 2020 Feb 6;180(3):568-584.e23.

8. Lancet Neurol—科学家使用全外显子测序技术揭示肌张力障碍患者存在单基因遗传变异

Abstract

Background: Dystonia is a clinically andgeneticallyheterogeneous condition that occurs in isolation (isolateddystonia), incombination with other movement disorders (combined dystonia), orin the contextof multisymptomatic phenotypes (isolated or combined dystoniawith otherneurological involvement). However, our understanding of itsaetiology is stillincomplete. We aimed to elucidate the monogenic causes forthe major clinicalcategories of dystonia.

Methods: For this exome-wide sequencing study,studyparticipants were identified at 33 movement-disorder andneuropaediatricspecialty centres in Austria, Czech Republic, France, Germany,Poland, Slovakia,and Switzerland. Each individual with dystonia was diagnosedin accordance withthe dystonia consensus definition. Index cases were eligiblefor this study ifthey had no previous genetic diagnosis and no indication of anacquired causeof their illness. The second criterion was not applied to asubset ofparticipants with a working clinical diagnosis of dystonic cerebralpalsy.Genomic DNA was extracted from blood of participants and whole-exomesequenced.To find causative variants in known disorder-associated genes, all variantswerefiltered, and unreported variants were classified according to AmericanCollegeof Medical Genetics and Genomics guidelines. All considered variantswerereviewed in expert round-table sessions to validate their clinicalsignificance.Variants that survived filtering and interpretation procedureswere defined asdiagnostic variants. In the cases that went undiagnosed,candidatedystonia-causing genes were prioritised in a stepwise workflow.

Findings: We sequenced the exomes of 764individuals withdystonia and 346 healthy parents who were recruited betweenJune 1, 2015, andJuly 31, 2019. We identified causative or probable causativevariants in 135(19%) of 728 families, involving 78 distinct monogenicdisorders. We observed alarger proportion of individuals with diagnosticvariants in those with dystonia(either isolated or combined) with coexistingnon-movement disorder-relatedneurological symptoms (100 [45%] of 222;excepting cases with evidence ofperinatal brain injury) than in those withcombined (19 [19%] of 98) or isolated(16 [4%] of 388) dystonia. Across allcategories of dystonia, 104 (65%) of the160 detected variants affected geneswhich are associated withneurodevelopmental disorders. We found diagnosticvariants in 11 genes notpreviously linked to dystonia, and propose apredictive clinical score thatcould guide the implementation of exomesequencing in routine diagnostics. Incases without perinatal sentinel events,genomic alterations contributedsubstantively to the diagnosis of dystoniccerebral palsy. In 15 families, wedelineated 12 candidate genes. These includeIMPDH2, encoding a key purinebiosynthetic enzyme, for which robust evidenceexisted for its involvement in aneurodevelopmental disorder with dystonia. Weidentified six variants in IMPDH2,collected from four independent cohorts,that were predicted to be deleteriousde-novo variants and expected to resultin deregulation of purine metabolism.

Interpretation: In this study, we have determinedthe roleof monogenic variants across the range of dystonic disorders,providing guidancefor the introduction of personalised care strategies andfostering follow-uppathophysiological explorations.

参考文献：Monogenicvariants in dystonia: an exome-widesequencing study. Lancet Neurol. 2020Nov;19(11):908-918.

9.    Nature medicine—散发性先天性脑积水的致病基因找到了：神经-胶质细胞发育相关基因异常是重要致病基础（附语音解读）

Abstract

Congenital hydrocephalus (CH), characterizedby enlargedbrain ventricles, is considered a disease of excessivecerebrospinal fluid (CSF)accumulation and thereby treated with neurosurgicalCSF diversion with highmorbidity and failure rates. The poorneurodevelopmental outcomes andpersistence of ventriculomegaly in somepost-surgical patients highlight ourlimited knowledge of disease mechanisms.Through whole-exome sequencing of 381 patients(232 trios) with sporadic,neurosurgically treated CH, we found that damaging denovo mutations account for>17% of cases, with five different genesexhibiting a significant de novomutation burden. In all, rare, damagingmutations with large effect contributedto ~22% of sporadic CH cases. MultipleCH genes are key regulators of neuralstem cell biology and converge in humantranscriptional networks and cell typespertinent for fetal neuro-gliogenesis.These data implicate genetic disruptionof early brain development, not impairedCSF dynamics, as the primarypathomechanism of a significant number of patientswith sporadic CH.

参考文献：Exomesequencing implicates genetic disruptionof prenatal neuro-gliogenesis insporadic congenital hydrocephalus. Nat Med.2020 Nov;26(11):1754-1765.

10.   Lancet Neurol—科学家使用全基因组关联分析揭示散发性克雅氏病的致病性遗传位点

Abstract

Background: Human prion diseases are rare andusuallyrapidly fatal neurodegenerative disorders, the most common beingsporadicCreutzfeldt-Jakob disease (sCJD). Variants in the PRNP gene thatencodes prionprotein are strong risk factors for sCJD but, although thecondition has similarheritability to other neurodegenerative disorders, noother genetic risk locihave been confirmed. We aimed to discover new geneticrisk factors for sCJD, andtheir causal mechanisms.

Methods: We did a genome-wide associationstudy of sCJD inEuropean ancestry populations (patients diagnosed withprobable or definite sCJDidentified at national CJD referral centres) with atwo-stage study design usinggenotyping arrays and exome sequencing.Conditional, transcriptional, andhistological analyses of implicated genes andproteins in brain tissues, andtests of the effects of risk variants onclinical phenotypes, were done using deeplongitudinal clinical cohort data.Control data from healthy individuals wereobtained from publicly availabledatasets matched for country.

Findings: Samples from 5208 cases wereobtained between1990 and 2014. We found 41 genome-wide significant singlenucleotidepolymorphisms (SNPs) and independently replicated findings at threelociassociated with sCJD risk; within PRNP (rs1799990; additive model oddsratio[OR] 1·23 [95% CI 1·17-1·30], p=2·68 × 10-15; heterozygous model p=1·01×10-135), STX6 (rs3747957; OR 1·16 [1·10-1·22], p=9·74 × 10-9), andGAL3ST1(rs2267161; OR 1·18 [1·12-1·25], p=8·60 × 10-10). Follow-up analysesshowedthat associations at PRNP and GAL3ST1 are likely to be caused bycommonvariants that alter the protein sequence, whereas risk variants in STX6areassociated with increased expression of the major transcriptsindisease-relevant brain regions.

Interpretation: We present, to our knowledge,the firstevidence of statistically robust genetic associations in sporadichuman priondisease that implicate intracellular trafficking and sphingolipidmetabolism asmolecular causal mechanisms. Risk SNPs in STX6 are shared withprogressivesupranuclear palsy, a neurodegenerative disease associated withmisfolding ofprotein tau, indicating that sCJD might share the same causalmechanisms asprion-like disorders.

参考文献：Identificationof novel risk loci and causalinsights for sporadic Creutzfeldt-Jakob disease: agenome-wide associationstudy. Lancet Neurol. 2020 Oct;19(10):840-848.

语音解读（具体见链接）

2020年十大研究进展名录

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）

7. 年终盘点：2019年脑血管病领域十大基础研究进展

8. 年终盘点：2019年神经炎症领域十大基础研究进展

9. 年终盘点：2019年神经活动记录十大基础研究进展

10. 年终盘点：2019年ALS/FTD十大基础研究进展

11. 年终盘点：2019年医学和生物学领域深度学习和神经网络十大基础研究进展

12. 年终盘点：2019年神经内科十大临床研究突破

13. 年终盘点：2019年疼痛防治和痛觉机制十大研究突破

14. 年终盘点：2019年睡眠和失眠领域十大研究突破

15.年终盘点：2019年神经发育及成年神经再生十大研究突破

16. 年终盘点：2019年大脑学习和记忆的十大研究突破

17. 年终盘点：2019年衰老和长寿十大研究突破

18. 年终盘点：2019年自闭症十大研究突破

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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20个神经科学领域的突破可能获得诺贝尔奖

1. 意识研究：意识的本质、组成、运行机制及其物质载体；不同意识层次的操控和干预，意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控：记忆的形成和消退机制，记忆的人为移植和记忆的人为消除等；

3. 痴呆研究：阿尔茨海默病的机制和治疗研究，血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究：喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究：性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究，包括脑卒中、脊髓损伤机制研究，神经干细胞移植研究，新型神经修复技术，神经康复技术。

13. 精神类疾病的机制和干预研究：自闭症、精分、抑郁症、智能障碍、药物成瘾等；

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究，包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术：光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究，包括脑机接口、神经刺激芯片、记忆存储芯片，意识存储芯片，人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术：包括任何机械肢体的人类移植，大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术：高分辨率成像技术、大型电极微阵列技术等。

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