Publications by authors named "Margit Burmeister"

107 Publications

Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.

J Med Genet 2021 Oct 16. Epub 2021 Oct 16.

Institute of Medical Genetics, University of Zurich, Zurich, Switzerland.

Background: Human coenzyme Q4 (COQ4) is essential for coenzyme Q (CoQ) biosynthesis. Pathogenic variants in cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency.

Methods: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed.

Results: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in . Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ and elevated levels of the metabolic intermediate 6-demethoxyubiquinone.

Conclusion: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of variants. Due to the insufficient clinical response to oral CoQ supplementation, alternative treatment strategies are warranted.
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http://dx.doi.org/10.1136/jmedgenet-2021-107729DOI Listing
October 2021

The Genetic Architecture of Depression in Individuals of East Asian Ancestry: A Genome-Wide Association Study.

JAMA Psychiatry 2021 Nov;78(11):1258-1269

23andme, Inc, Sunnyvale, California.

Importance: Most previous genome-wide association studies (GWAS) of depression have used data from individuals of European descent. This limits the understanding of the underlying biology of depression and raises questions about the transferability of findings between populations.

Objective: To investigate the genetics of depression among individuals of East Asian and European descent living in different geographic locations, and with different outcome definitions for depression.

Design, Setting, And Participants: Genome-wide association analyses followed by meta-analysis, which included data from 9 cohort and case-control data sets comprising individuals with depression and control individuals of East Asian descent. This study was conducted between January 2019 and May 2021.

Exposures: Associations of genetic variants with depression risk were assessed using generalized linear mixed models and logistic regression. The results were combined across studies using fixed-effects meta-analyses. These were subsequently also meta-analyzed with the largest published GWAS for depression among individuals of European descent. Additional meta-analyses were carried out separately by outcome definition (clinical depression vs symptom-based depression) and region (East Asian countries vs Western countries) for East Asian ancestry cohorts.

Main Outcomes And Measures: Depression status was defined based on health records and self-report questionnaires.

Results: There were a total of 194 548 study participants (approximate mean age, 51.3 years; 62.8% women). Participants included 15 771 individuals with depression and 178 777 control individuals of East Asian descent. Five novel associations were identified, including 1 in the meta-analysis for broad depression among those of East Asian descent: rs4656484 (β = -0.018, SE = 0.003, P = 4.43x10-8) at 1q24.1. Another locus at 7p21.2 was associated in a meta-analysis restricted to geographically East Asian studies (β = 0.028, SE = 0.005, P = 6.48x10-9 for rs10240457). The lead variants of these 2 novel loci were not associated with depression risk in European ancestry cohorts (β = -0.003, SE = 0.005, P = .53 for rs4656484 and β = -0.005, SE = 0.004, P = .28 for rs10240457). Only 11% of depression loci previously identified in individuals of European descent reached nominal significance levels in the individuals of East Asian descent. The transancestry genetic correlation between cohorts of East Asian and European descent for clinical depression was r = 0.413 (SE = 0.159). Clinical depression risk was negatively genetically correlated with body mass index in individuals of East Asian descent (r = -0.212, SE = 0.084), contrary to findings for individuals of European descent.

Conclusions And Relevance: These results support caution against generalizing findings about depression risk factors across populations and highlight the need to increase the ancestral and geographic diversity of samples with consistent phenotyping.
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http://dx.doi.org/10.1001/jamapsychiatry.2021.2099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482304PMC
November 2021

Genomic heterogeneity affects the response to Daylight Saving Time.

Sci Rep 2021 07 20;11(1):14792. Epub 2021 Jul 20.

Michigan Neuroscience Institute, University of Michigan, Ann Arbor, MI, 48109, USA.

Circadian clocks control the timing of many physiological events in the 24-h day. When individuals undergo an abrupt external shift (e.g., change in work schedule or travel across multiple time zones), circadian clocks become misaligned with the new time and may take several days to adjust. Chronic circadian misalignment, e.g., as a result of shift work, has been shown to lead to several physical and mental health problems. Despite the serious health implications of circadian misalignment, relatively little is known about how genetic variation affects an individual's ability to entrain to abrupt external changes. Accordingly, we used the one-hour advance from the onset of daylight saving time (DST) as a natural experiment to comprehensively study how individual heterogeneity affects the shift of sleep/wake cycles in response to an abrupt external time change. We found that individuals genetically predisposed to a morning tendency adjusted to the advance in a few days, while genetically predisposed evening-inclined individuals had not shifted. Observing differential effects by genetic disposition after a one-hour advance underscores the importance of heterogeneity in adaptation to external schedule shifts. These genetic differences may affect how individuals adjust to jet lag or shift work as well.
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http://dx.doi.org/10.1038/s41598-021-94459-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292316PMC
July 2021

Vmp1, Vps13D, and Marf/Mfn2 function in a conserved pathway to regulate mitochondria and ER contact in development and disease.

Curr Biol 2021 Jul 20;31(14):3028-3039.e7. Epub 2021 May 20.

Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address:

Mutations in Vps13D cause defects in autophagy, clearance of mitochondria, and human movement disorders. Here, we discover that Vps13D functions in a pathway downstream of Vmp1 and upstream of Marf/Mfn2. Like vps13d, vmp1 mutant cells exhibit defects in autophagy, mitochondrial size, and clearance. Through the relationship between vmp1 and vps13d, we reveal a novel role for Vps13D in the regulation of mitochondria and endoplasmic reticulum (ER) contact. Significantly, the function of Vps13D in mitochondria and ER contact is conserved between fly and human cells, including fibroblasts derived from patients suffering from VPS13D mutation-associated neurological symptoms. vps13d mutants have increased levels of Marf/MFN2, a regulator of mitochondrial fusion. Importantly, loss of marf/MFN2 suppresses vps13d mutant phenotypes, including mitochondria and ER contact. These findings indicate that Vps13d functions at a regulatory point between mitochondria and ER contact, mitochondrial fusion and autophagy, and help to explain how Vps13D contributes to disease.
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http://dx.doi.org/10.1016/j.cub.2021.04.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319081PMC
July 2021

Maternal Overweight and Obesity during Pregnancy Are Associated with Neonatal, but Not Maternal, Hepcidin Concentrations.

J Nutr 2021 Aug;151(8):2296-2304

Department of Pediatrics, Medical School, University of Michigan, Ann Arbor, MI, USA.

Background: Overweight or obesity among pregnant women may compromise maternal and neonatal iron status by upregulating hepcidin.

Objectives: This study determined the association of 1) maternal and neonatal iron status with maternal and neonatal hepcidin concentrations, and 2) maternal prepregnancy weight status with maternal and neonatal hepcidin concentrations.

Methods: We examined hematologic data from 405 pregnant women and their infants from the placebo treatment group of a pregnancy iron supplementation trial in rural China. We measured hepcidin, serum ferritin (SF), soluble transferrin receptor (sTfR), and high-sensitivity C-reactive protein in maternal blood samples at mid-pregnancy and in cord blood at delivery. We used regression analysis to examine the association of maternal prepregnancy overweight or obese status with maternal hepcidin concentration in mid-pregnancy and cord hepcidin concentrations. We also used path analysis to examine mediation of the association of maternal prepregnancy overweight or obese status with maternal iron status by maternal hepcidin, as well as with neonatal hepcidin by neonatal iron status.

Results: Maternal iron status was positively correlated with maternal hepcidin at mid-pregnancy (SF: r = 0.63, P < 0.001; sTfR: r = -0.37, P < 0.001). Neonatal iron status was also positively correlated with cord hepcidin (SF: r = 0.61, P < 0.001; sTfR: r = -0.39, P < 0.001). In multiple linear regression models, maternal prepregnancy overweight or obese status was not associated with maternal hepcidin at mid-pregnancy but was associated with lower cord hepcidin (coefficient = -0.21, P = 0.004). Using path analysis, we observed a significant indirect effect of maternal prepregnancy overweight or obese status on cord hepcidin, mediated by neonatal iron status.

Conclusions: In both pregnant women and neonates, hepcidin was responsive to iron status. Maternal prepregnancy overweight status, with or without including obese women, was associated with lower cord blood hepcidin, likely driven by lower iron status among the neonates of these mothers.
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http://dx.doi.org/10.1093/jn/nxab133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349130PMC
August 2021

β-Arrestin 2 (ARRB2) Polymorphism is Associated With Adverse Consequences of Chronic Heroin Use.

Am J Addict 2021 07 30;30(4):351-357. Epub 2021 Mar 30.

Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, Michigan.

Background And Objectives: β-arrestin 2 is an intracellular protein recruited during the activation of G-protein-coupled receptors. In preclinical studies, β-arrestin 2 has been implicated in µ-opioid receptor desensitization and internalization and the development of opioid tolerance and dependence. The present study investigated relationships between variants in the gene encoding β-arrestin 2 (ARRB2) and clinically relevant phenotypes among individuals with opioid use disorder (OUD). We hypothesized that ARRB2 variants would be associated with the negative effects of long-term heroin use.

Methods: Chronic heroin users (N = 201; n = 103 African American; n = 98 Caucasian) were genotyped for ARRB2 r1045280 (synonymous, also affecting binding motif of transcription factor GTF2IRD1), rs2036657 (3'UTR) and rs3786047 (intron) and assessed for the past-month frequency of use, injection use, and lifetime duration of heroin use, number of heroin quit-attempts, and heroin use-related consequences.

Results: Lifetime heroin-use consequences (especially occupational and health-related) were significantly lower for African American ARRB2 r1045280 C-allele carriers compared with the TT genotype. There was no significant genotype difference in the Caucasian group. ARRB2 rs2036657 was in strong linkage disequilibrium with rs1045280.

Discussion And Conclusions: These results, consistent with extant data, illustrate a role for ancestry-dependent allelic variation in ARRB2 r1045280 on heroin-use consequences. The ARRB2 r1045280 C-allele played a protective role in African-descent participants.

Scientific Significance: These first-in-human findings, which should be replicated, provide support for mechanistic investigations of ARRB2 and related intracellular signaling molecules in OUD etiology, treatment, and relapse prevention. (Am J Addict 2021;00:00-00).
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http://dx.doi.org/10.1111/ajad.13150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243774PMC
July 2021

Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.

J Hum Genet 2021 Aug 18;66(8):761-768. Epub 2021 Feb 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.
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http://dx.doi.org/10.1038/s10038-020-00896-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310791PMC
August 2021

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Mol Psychiatry 2021 Sep 22;26(9):5239-5250. Epub 2021 Jan 22.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.
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http://dx.doi.org/10.1038/s41380-020-01006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295400PMC
September 2021

Review and Consensus on Pharmacogenomic Testing in Psychiatry.

Pharmacopsychiatry 2021 Jan 4;54(1):5-17. Epub 2020 Nov 4.

Division of Clinical Pharmacology, Toxicology & Therapeutic Innovation, Children's Mercy Kansas City, Kansas City and School of Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (), oxcarbazepine (), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes () is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.
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http://dx.doi.org/10.1055/a-1288-1061DOI Listing
January 2021

Sequence Variants in the and Genes Underlying Isolated Split-Hand/Split-Foot Malformation.

Genet Test Mol Biomarkers 2020 Sep 7;24(9):600-607. Epub 2020 Aug 7.

Department of Biochemistry, Abdul Wali Khan University, Mardan, Pakistan.

Split-hand/split-foot malformation (SHFM) is a developmental and congenital limb malformation characterized by variable degrees of medial clefting or absence of one or more digits in hands and/or feet. The aim of this study was to identify the underlying cause of three consanguineous Pakistani families showing various types of SHFM-related features. Standard molecular methods, including whole-genome sequencing (WGS), whole-exome sequencing (WES), microsatellite markers-based genotyping, and Sanger sequencing were performed to search for the likely causative variants. In family A, WES revealed a novel homozygous missense variant [c.338G>A, p.(Gly113Asp)] in the gene. In family B, microsatellite-based genotyping followed by Sanger sequencing revealed a novel homozygous 13 base pairs deletion [c.884-896delTCCAGCCCCGTCT, p.(Phe295Cysfs*87)] in the same gene. In family C, WGS divulged a previously reported heterozygous missense variant [c.956G>A, p.(Arg319His)] in the gene. Mapping and sequencing genes and variants for severe skeletal disorders, such as SHRM, will facilitate establishing specific genotype-phenotype correlations and providing genetic counseling for the families suffering from such conditions.
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http://dx.doi.org/10.1089/gtmb.2020.0024DOI Listing
September 2020

A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome.

Eur J Hum Genet 2020 10 1;28(10):1422-1431. Epub 2020 Jun 1.

Clinical Geneticist Medical Genetics Department, CHUQ-CHUL, Quebec, Canada.

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.
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http://dx.doi.org/10.1038/s41431-020-0654-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608102PMC
October 2020

When Genetics Meets Religion: What Scientists and Religious Leaders Can Learn from Each Other.

Public Health Genomics 2019 4;22(5-6):174-188. Epub 2019 Dec 4.

Department of Health Management and Policy, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.

Introduction: To date scientists and religious leaders have not yet engaged in sustained face-to-face conversation concerning precision public health-related genetic technologies.

Objectives: To elucidate areas of commonality and divergence in scientists' and religious leaders' views of precision genetic technologies, and extract lessons conveyed by religious leaders to scientists, and scientists to religious leaders through participatory dialogue.

Methods: Six 1.5-h dialogue sessions were held between 6 religious leaders, 8 University of Michigan scientists, and 3 additional public health/genetic counseling graduate students between October 2016 and September 2017, followed by an open conference at the Ann Arbor Public Library (n = 46). Statements were organized into thematically arranged duets comparing views of scientists and religious leaders. Duets were further ordered into interpretive levels. Comparative techniques were used to assure category agreement and face validity.

Results: The analysis yielded 20 duets and 3 interpretive levels (expositional; implications and consequences; and integrative, bridging concepts). Scientists emphasized the value of epigenetic testing for health promotion, and cost saving for some forms of early genetic testing for adult-onset conditions. Religious leaders stressed care for an individual's willingness to change over technical fixes for behavioral conditions and, together with public participants, the importance of allocating money for societal needs. Both expressed caution on the use of nuclear transfer for mitochondrial DNA replacement and secondary uses of genetic data. Lay conference participants pointed towards a middle ground on the release of genetically edited mosquitoes for disease eradication.

Discussion: Scientists stressed the value of professional guidance; religious leaders listened to family needs. Dialogues met four literature-based criteria for stakeholder involvement in deliberative processes.

Conclusion: While scientists and religious leaders differ in their points of emphasis and faith orientations (professional competency versus drawing on compassion), they can successfully collaborate in reaching mutual understanding and specific areas of agreement on precision genetic technologies relating to public health.
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http://dx.doi.org/10.1159/000504261DOI Listing
May 2020

Genomic prediction of depression risk and resilience under stress.

Nat Hum Behav 2020 01 28;4(1):111-118. Epub 2019 Oct 28.

Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.

Advancing ability to predict who is likely to develop depression holds great potential in reducing the disease burden. Here, we use the predictable and large increase in depression with physician training stress to identify predictors of depression. Applying the major depressive disorder polygenic risk score (MDD-PRS) derived from the most recent Psychiatric Genomics Consortium-UK Biobank-23andMe genome-wide association study to 5,227 training physicians, we found that MDD-PRS predicted depression under training stress (β = 0.095, P = 4.7 × 10) and that MDD-PRS was more strongly associated with depression under stress than at baseline (MDD-PRS × stress interaction β = 0.036, P = 0.005). Further, known risk factors accounted for substantially less of the association between MDD-PRS and depression when under stress than at baseline, suggesting that MDD-PRS adds unique predictive power in depression prediction. Finally, we found that low MDD-PRS may have particular use in identifying individuals with high resilience. Together, these findings suggest that MDD-PRS holds promise in furthering our ability to predict vulnerability and resilience under stress.
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http://dx.doi.org/10.1038/s41562-019-0759-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980948PMC
January 2020

Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.

Am J Hum Genet 2019 11 3;105(5):996-1004. Epub 2019 Oct 3.

Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam 1081 HV, the Netherlands. Electronic address:

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848986PMC
November 2019

Heroin delay discounting and impulsivity: Modulation by DRD1 genetic variation.

Addict Biol 2020 05 13;25(3):e12777. Epub 2019 Jun 13.

School of Medicine, Wayne State University, Detroit, Michigan.

Background: Dopamine D1 receptors (encoded by DRD1) are implicated in drug addiction and high-risk behaviors. Delay discounting (DD) procedures measure decisional balance between choosing smaller/sooner rewards vs larger/later rewards. Individuals with higher DD (rapid discounting) are prone to maladaptive behaviors that provide immediate reinforcement (eg, substance use). DRD1 variants have been linked with increased DD (in healthy volunteers) and opioid abuse. This study determined whether four dopaminergic functional variants modulated heroin DD and impulsivity.

Methods: Substance use, DD, and genotype data (DRD1 rs686 and rs5326, DRD3 rs6280, COMT rs4680) were obtained from 106 current heroin users. Subjects completed an array of DD choices during two imagined conditions: heroin satiation and withdrawal. Rewards were expressed as $10 heroin bag units, with maximum delayed amount of 30 bags. Delays progressively increased from 3 to 96 hours.

Results: DRD1 rs686 (A/A, n = 25; G/A, n = 56; G/G, n = 25) was linearly related to the difference in heroin DD (area under the curve; AUC) between the heroin satiation and withdrawal conditions; specifically, G/G homozygotes had a significantly smaller (satiation minus withdrawal) AUC difference score had higher drug-use impulsivity questionnaire scores, relative to A/A homozygotes, with G/A intermediate. DRD3 and COMT variants were not associated with these DD and impulsivity outcomes.

Conclusion: DRD1 rs686 modulated the difference in heroin DD score between pharmacological states and was associated with drug-use impulsivity. These data support a role of DRD1 in opioid DD and impulsive behaviors.
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http://dx.doi.org/10.1111/adb.12777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908785PMC
May 2020

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Nat Genet 2019 05 1;51(5):793-803. Epub 2019 May 1.

Department of Psychiatry, Weill Cornell Medical College, New York, NY, USA.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.
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http://dx.doi.org/10.1038/s41588-019-0397-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956732PMC
May 2019

Cognitive Control as a 5-HT-Based Domain That Is Disrupted in Major Depressive Disorder.

Front Psychol 2019 29;10:691. Epub 2019 Mar 29.

The Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.
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http://dx.doi.org/10.3389/fpsyg.2019.00691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450211PMC
March 2019

COQ4 Mutation Leads to Childhood-Onset Ataxia Improved by CoQ10 Administration.

Cerebellum 2019 Jun;18(3):665-669

Molecular & Behavioral Neuroscience Institute, University of Michigan, 5061 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, USA.

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http://dx.doi.org/10.1007/s12311-019-01011-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536000PMC
June 2019

Loss of the sphingolipid desaturase DEGS1 causes hypomyelinating leukodystrophy.

J Clin Invest 2019 03 11;129(3):1240-1256. Epub 2019 Feb 11.

Department of Clinical Genomics and.

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.
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http://dx.doi.org/10.1172/JCI123959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391109PMC
March 2019

BaiHui: cross-species brain-specific network built with hundreds of hand-curated datasets.

Bioinformatics 2019 07;35(14):2486-2488

Department of Computational Medicine and Bioinformatics.

Motivation: Functional gene networks, representing how likely two genes work in the same biological process, are important models for studying gene interactions in complex tissues. However, a limitation of the current network-building scheme is the lack of leveraging evidence from multiple model organisms as well as the lack of expert curation and quality control of the input genomic data.

Results: Here, we present BaiHui, a brain-specific functional gene network built by probabilistically integrating expertly-hand-curated (by reading original publications) heterogeneous and multi-species genomic data in human, mouse and rat brains. To facilitate the use of this network, we deployed a web server through which users can query their genes of interest, visualize the network, gain functional insight from enrichment analysis and download network data. We also illustrated how this network could be used to generate testable hypotheses on disease gene prioritization of brain disorders.

Availability And Implementation: BaiHui is freely available at: http://guanlab.ccmb.med.umich.edu/BaiHui/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/bty1001DOI Listing
July 2019

Neuropeptide Y and representation of salience in human nucleus accumbens.

Neuropsychopharmacology 2019 02 2;44(3):495-502. Epub 2018 Oct 2.

University of Utah, Salt Lake City, UT, 84108, USA.

Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring low NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.
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http://dx.doi.org/10.1038/s41386-018-0230-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333772PMC
February 2019

Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.

Genet Med 2019 01 18;21(1):195-206. Epub 2018 Jun 18.

Department of Human Genetics, The University of Chicago, Chicago, IL, USA.

Purpose: To examine the impact of a targeted exome approach for the molecular diagnosis of patients nationwide with a wide range of ataxia-related phenotypes.

Methods: One hundred and seventy patients with ataxia of unknown etiology referred from clinics throughout the United States and Canada were studied using a targeted exome approach. Patients ranged in age from 2 to 88 years. Analysis was focused on 441 curated genes associated with ataxia and ataxia-like conditions.

Results: Pathogenic and suspected diagnostic variants were identified in 88 of the 170 patients, providing a positive molecular diagnostic rate of 52%. Forty-six different genes were implicated, with the six most commonly mutated genes being SPG7, SYNE1, ADCK3, CACNA1A, ATP1A3, and SPTBN2, which accounted for >40% of the positive cases. In many cases a diagnosis was provided for conditions that were not suspected and resulted in the broadening of the clinical spectrum of several conditions.

Conclusion: Exome sequencing with targeted analysis provides a high-yield approach for the genetic diagnosis of ataxia-related conditions. This is the largest targeted exome study performed to date in patients with ataxia and ataxia-like conditions and represents patients with a wide range of ataxia phenotypes typically encountered in neurology and genetics clinics.
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http://dx.doi.org/10.1038/s41436-018-0007-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524765PMC
January 2019

Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability.

Front Mol Neurosci 2018 4;11:104. Epub 2018 Apr 4.

Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States.

Intellectual disability (ID) affects up to 2% of the population world-wide and often coincides with other neurological conditions such as autism spectrum disorders. Mutations in cause Mental Retardation, X-linked, Syndromic, Claes-Jensen type (MRXSCJ, OMIM #300534) and are one of the most common causes of X-linked ID. encodes a histone demethylase for di- and tri-methylated histone H3 lysine 4 (H3K4me2/3), which are enriched in transcriptionally engaged promoter regions. KDM5C regulates gene transcription; however, it remains unknown whether removal of H3K4me is fully responsible for KDM5C-mediated gene regulation. Most mutations functionally tested to date result in reduced enzymatic activity of KDM5C, indicating loss of demethylase function as the primary mechanism underlying MRXSCJ. Here, we report a novel KDM5C mutation, R1115H, identified in an individual displaying MRXSCJ-like symptoms. The carrier mother's cells exhibited a highly skewed X-inactivation pattern. The KDM5C-R1115H substitution does not have an impact on enzymatic activity nor protein stability. However, when overexpressed in post-mitotic neurons, KDM5C-R1115H failed to fully suppress expression of target genes, while the mutant also affected expression of a distinct set of genes compared to KDM5C-wildtype. These results suggest that KDM5C may have non-enzymatic roles in gene regulation, and alteration of these roles contributes to MRXSCJ in this patient.
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http://dx.doi.org/10.3389/fnmol.2018.00104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893713PMC
April 2018

Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.

Ann Neurol 2018 06 30;83(6):1075-1088. Epub 2018 Jun 30.

Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI.

Objective: To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia.

Methods: In an international collaboration, we independently performed exome sequencing in 7 families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knockout model and investigated mitochondrial function in patient-derived fibroblast cultures.

Results: Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all 7 families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4 (SCAR4). Linkage to chromosome 1p36 was found in this family with a logarithm of odds score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but 2 patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knockdown or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production.

Interpretation: Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. Ann Neurol 2018.
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http://dx.doi.org/10.1002/ana.25220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105379PMC
June 2018

Brain-specific functional relationship networks inform autism spectrum disorder gene prediction.

Transl Psychiatry 2018 03 6;8(1):56. Epub 2018 Mar 6.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.

Autism spectrum disorder (ASD) is a neuropsychiatric disorder with strong evidence of genetic contribution, and increased research efforts have resulted in an ever-growing list of ASD candidate genes. However, only a fraction of the hundreds of nominated ASD-related genes have identified de novo or transmitted loss of function (LOF) mutations that can be directly attributed to the disorder. For this reason, a means of prioritizing candidate genes for ASD would help filter out false-positive results and allow researchers to focus on genes that are more likely to be causative. Here we constructed a machine learning model by leveraging a brain-specific functional relationship network (FRN) of genes to produce a genome-wide ranking of ASD risk genes. We rigorously validated our gene ranking using results from two independent sequencing experiments, together representing over 5000 simplex and multiplex ASD families. Finally, through functional enrichment analysis on our highly prioritized candidate gene network, we identified a small number of pathways that are key in early neural development, providing further support for their potential role in ASD.
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http://dx.doi.org/10.1038/s41398-018-0098-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5838237PMC
March 2018

Pathways to Youth Behavior: The Role of Genetic, Neural, and Behavioral Markers.

J Res Adolesc 2018 03;28(1):26-39

University of Michigan.

Neural and temperamental mechanisms through which a genetic risk marker in the γ-amino butyric acid α2 receptor subunit (GABRA2) impacts adolescent functioning were investigated. Participants (N = 80; 29 female) completed an emotional word task during functional magnetic resonance imaging. Behavioral control, negative emotionality, and resiliency temperament constructs were assessed. Externalizing and internalizing problems were the outcomes. Those with the GABRA2 minor allele had reduced activation to positive words in the angular gyrus, middle temporal gyrus, and cerebellum, and to negative words in frontal, parietal, and occipital cortices. Reduced activation in the angular gyrus predicted greater negative emotionality and, in turn, elevated externalizing problems. Reduced activation in the inferior parietal cortex predicted greater resiliency and, in turn, low externalizing problems.
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http://dx.doi.org/10.1111/jora.12341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823277PMC
March 2018

The recurrent mutation in TMEM106B also causes hypomyelinating leukodystrophy in China and is a CpG hotspot.

Brain 2018 05;141(5):e36

Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA.

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http://dx.doi.org/10.1093/brain/awy029DOI Listing
May 2018

Biological underpinnings of an internalizing pathway to alcohol, cigarette, and marijuana use.

J Abnorm Psychol 2018 01 27;127(1):79-91. Epub 2017 Nov 27.

Department of Psychiatry, University of Michigan.

There is a limited understanding as to how specific genes impact addiction risk. Applying a developmental framework and research domain criteria (RDoC) to identify etiological pathways from genetic markers to addiction may have utility. Prior research has largely focused on externalizing pathways to substance use. Although internalizing mechanisms have received less attention, there is strong support that addiction is a longer term consequence of using substances to cope with internalizing as well as externalizing problems. This study tests whether temperament and depression mediate the association between specific genetic variants and substance use. The sample consisted of 426 adolescents from the Michigan Longitudinal Study (70.9% boys, 84.0% White). Four specific genetic variants were examined: SLC6A4 (5HTTLPR), BDNF (rs6265), NPY (rs3037354), and CRHBP (rs7728378). Childhood resiliency and behavioral control were examined as potential mediators, in addition to early adolescent depression, using a multiple-mediator path model. Resiliency and depression were supported as mediators in the association between genetic risk and later substance use. Important differences emerged across substances of abuse. Indirect effects via depression were not significant with the inclusion of aggression. Early difficulties with emotional coping may represent nonspecific neurobiological underpinnings for an internalizing pathway to addiction. (PsycINFO Database Record
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http://dx.doi.org/10.1037/abn0000310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785427PMC
January 2018
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