Publications by authors named "Lorraine Clark"

Polygenic risk scores (PRSs) assess genetic susceptibility to alcohol use disorder (AUD), yet their molecular implications remain underexplored. Neuroimmune interactions, particularly in microglia, are recognized as notable contributors to AUD pathophysiology. We investigated the interplay between AUD PRS and ethanol in human microglia derived from iPSCs from individuals with AUD high-PRS (diagnosed with AUD) or low-PRS (unaffected).

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After centuries of relative stability, the scientific publishing world has undergone tremendous disruption and change during the first decades of the 21st century. The causes for disruption can be traced to the information revolution, which brought such benefits as rapid publication, greater connectivity, and ready access to large databases, along with less desirable practices including image manipulation, plagiarism, and other ethical transgressions. The information revolution has driven the proliferation of journals, expansion of for-profit academic publishing, and empowerment of the open-access movement, each of which has exerted new financial pressures on traditional publishing models.

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Article Synopsis
  • - The study aimed to create a global cohort of individuals with Parkinson's disease (PD) linked to specific genetic variants, aiming to improve the understanding and treatment of monogenic PD.
  • - Researchers collected data from 3,888 participants across 92 centers in 42 countries, including 3,185 diagnosed with PD and 703 unaffected individuals, which highlighted a total of 269 distinct pathogenic variants.
  • - This initiative not only established the largest international genetic PD cohort but also provided quality-controlled clinical and genetic data to foster further research collaboration.
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Background: Essential tremor (ET), one of the most common neurological disorders, has a phenotypically heterogeneous presentation characterized by bilateral kinetic tremor of the arms and, in some patients, tremor involving other body regions (e.g., head, voice).

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Background: Essential tremor (ET) is a highly prevalent neurological disease that frequently runs in families. A recent and controversial proposal is to separate ET patients into two distinct groups - ET versus ET-plus. If this were a valid construct, one would expect in familial aggregation studies to observe that ET-plus would cluster in some families yet be absent in others, rather than being randomly distributed across families.

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Inherited retinal degenerations are clinically and genetically heterogeneous diseases characterized by progressive deterioration of vision. This study aimed at assessing the diagnostic yield of exome sequencing (ES) for an unselected cohort of individuals with hereditary retinal disorders. It is a retrospective study of 357 unrelated affected individuals, diagnosed with retinal disorders who underwent clinical ES.

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Background And Objectives: Essential tremor (ET) is one of the most prevalent movement disorders. Because ET is so common, individuals with other neurologic disorders may also have ET. There is evidence, however, that the cooccurrence of ET with Parkinson disease (PD) and/or dystonia is not merely a chance cooccurrence.

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Importance: Essential tremor (ET) is one of the most common movement disorders, affecting 5% of the general population older than 65 years. Common variants are thought to contribute toward susceptibility to ET, but no variants have been robustly identified.

Objective: To identify common genetic factors associated with risk of ET.

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Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease.

Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively.

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The identification of rare variants associated with schizophrenia has proven challenging due to genetic heterogeneity, which is reduced in founder populations. In samples from the Ashkenazi Jewish population, we report that schizophrenia cases had a greater frequency of novel missense or loss of function (MisLoF) ultra-rare variants (URVs) compared to controls, and the MisLoF URV burden was inversely correlated with polygenic risk scores in cases. Characterizing 141 "case-only" genes (MisLoF URVs in ≥3 cases with none in controls), the cadherin gene set was associated with schizophrenia.

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Article Synopsis
  • The genetic foundations of Lewy body dementia (LBD) remain unclear, prompting researchers to conduct whole-genome sequencing on both LBD patients and healthy individuals.
  • They discovered five distinct risk loci through genome-wide association analysis and identified mutations in the GBA gene as a significant factor.
  • The study suggests that LBD shares genetic risk factors and biological pathways with Alzheimer's and Parkinson's diseases, enhancing our understanding of this complex neurodegenerative disorder.
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Background: Decision support can help patients facing implantable cardioverter-defibrillator (ICD) replacement understand their options and reach an informed decision reflective of their preferences.

Objective: The aim of this study was to evaluate the feasibility of a decision support intervention for patients faced with the decision to replace their ICD.

Methods: A pilot feasibility randomized trial was conducted.

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Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases.

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Essential tremor (ET) is one of the most common movement disorders. The etiology of ET remains largely unexplained. Whole genome sequencing (WGS) is likely to be of value in understanding a large proportion of ET with Mendelian and complex disease inheritance patterns.

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Tremor is the most common movement disorder; however, we are just beginning to understand the brain circuitry that generates tremor. Various neuroimaging, neuropathological, and physiological studies in human tremor disorders have been performed to further our knowledge of tremor. But, the causal relationship between these observations and tremor is usually difficult to establish and detailed mechanisms are not sufficiently studied.

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Article Synopsis
  • Recent genetic studies have revealed significant risk variants affecting dementia with Lewy bodies (DLB), showing that common variants explain a limited portion of its genetic basis.
  • The estimated heritability of DLB is significantly higher than past studies suggested, at 59.9%, indicating more complex genetic factors at play.
  • Genetic correlation analysis revealed DLB is positively associated with education levels, contrasting with the relationship found in Alzheimer's disease, suggesting the need for larger genome-wide association studies (GWAS) to uncover new genetic risk factors for DLB.
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Objective: To elucidate the genetic cause of a large 5 generation South Indian family with multiple individuals with predominantly an upper limb postural tremor and posturing in keeping with another form of tremor, namely, dystonic tremor.

Methods: Whole-genome single nucleotide polymorphism (SNP) microarray analysis was undertaken to look for copy number variants in the affected individuals.

Results: Whole-genome SNP microarray studies identified a tandem duplicated genomic segment of chromosome 15q24 present in all affected family members.

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Article Synopsis
  • SMPD1 gene variants, particularly p.L302P and p.fsP330, are associated with an increased risk of developing Parkinson's disease (PD) in certain populations, specifically the Ashkenazi Jewish cohort.
  • Analysis revealed that lower acid-sphingomyelinase activity in PD patients is linked to an earlier onset of the disease, indicating its potential role as a biomarker.
  • Experimental findings showed that SMPD1 mutations disrupt the normal function of acid-sphingomyelinase, leading to higher levels of α-synuclein in dopaminergic cells, which may contribute to the pathogenesis of PD.
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Mutations in the gene SCAPER (S-phase CyclinA Associated Protein residing in the Endoplasmic Reticulum) have recently been identified as causing syndromic autosomal recessive retinitis pigmentosa with the extraocular manifestations of intellectual disability and attention-deficit/hyperactivity disorder. We present the case of an 11-year-old boy that presented to our clinic with the complaint of decreased night vision. Clinical presentation, family history, and diagnostic imaging were congruent with the diagnosis of autosomal recessive retinitis pigmentosa.

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The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data.

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The search for genes for essential tremor (ET) is active. Researchers often depend on probands' reports or self-reports to assign disease status to relatives. Yet there are surprisingly few data on the validity of these reports.

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  • A study investigated transient head tremor in first-degree relatives of essential tremor (ET) cases to determine if it indicates early signs of ET or is a normal occurrence.
  • Among 241 relatives studied, 10.8% displayed isolated head tremor compared to only 2.6% of 77 spousal controls, suggesting a potential connection to ET in families.
  • The tremors were brief, occurring mainly during speech, and were different in quality from voluntary head shaking, leading researchers to believe they may signal undiagnosed ET, warranting further investigation.
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Essential Tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the US; the pathophysiology of the disorder is poorly understood. Recently, we identified a mutation (KCNS2 (Kv9.2), c.

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While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (≥ 30×), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population.

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