Reply to Tzoulis et al.: Genetic and clinical heterogeneity of essential tremor

Gulsuner, Hilal Unal; Gülsüner, Süleyman; Mercan, Fatma Nazli; Onat, Onur Emre; Walsh, Tom; Shahin, Hashem; Lee, Ming K.; Doğu, Okan; Kansu, Tülay; Topaloǧlu, Haluk; Elibol, Bülent; Akbostanci, Cenk; King, Mary Claire; Özçelık, Tayfun; Tekinay, Ayşe B.

doi:10.1073/pnas.1503756112

Cited by 3 publications

(3 citation statements)

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“…Using network propagation, we identified ARDs with incompletely understood pathogenesis where aging hallmarks may contribute to their development. Essential tremor has previously been associated with mitochondrial abnormalities, but the degree of their role is unclear (Louis, 2014;Unal Gulsuner et al, 2014). We found that essential tremor co-occurred with many ARDs strongly linked to mitochondrial dysfunction implying this is in fact a key pathogenic mechanism in essential tremor.…”

Section: Discussionmentioning

confidence: 70%

“…Essential tremor is a neurological disorder characterized by an involuntary, rhythmic tremor and was newly prioritized as a top 30 ARD associated with mitochondrial dysfunction (Figure S2a). It has previously been associated with mitochondrial abnormalities; however, the degree of their role is unclear (Unal Gulsuner et al, 2014). This disorder also has genetic evidence of association with five genes (i.e., STK32B, NAT2, LINGO1, CTNNA3, and LRRTM3) at genome-wide significance.…”

Section: Associations Of Aging Hallmarks With Ards With Incompletely ...mentioning

confidence: 99%

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Biological mechanisms of aging predict age‐related disease co‐occurrence in patients

et al. 2022

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Section: Discussionmentioning

confidence: 70%

Section: Associations Of Aging Hallmarks With Ards With Incompletely ...mentioning

confidence: 99%

Biological mechanisms of aging predict age‐related disease co‐occurrence in patients

et al. 2022

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“…However, systematic search for common variants influencing antipsychotic drug response by genome-wide association study so far has been unsuccessful. 6,7 The role of rare functional variants has been recognized in several neuropsychiatric disorders, including schizophrenia, [8][9][10][11][12] intellectual disability, [13][14][15] and autism spectrum disorder, [16][17][18] and in serotonin reuptake inhibitor treatment response in major depression. 19 Because most drugs exert their effects through protein binding, whole-exome sequencing (WES) offers a costeffective strategy for investigating rare variants in drugresponse studies.…”

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confidence: 99%

Effect of Damaging Rare Mutations in Synapse-Related Gene Sets on Response to Short-term Antipsychotic Medication in Chinese Patients With Schizophrenia

Wang

Yue

et al. 2018

JAMA Psychiatry

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; for the Chinese Antipsychotics Pharmacogenomics Consortium IMPORTANCE The underlying mechanism for individual differences in patient response to antipsychotic medication remains unknown. OBJECTIVE To discover genes and gene sets harboring rare variants associated with short-term antipsychotic medication efficacy. DESIGN, SETTING, AND PARTICIPANTS In this multicenter, open-label, randomized clinical trial conducted between July 6, 2010, and December 31, 2011, 3023 patients recruited in China of Chinese Han descent with schizophrenia with total Positive and Negative Syndrome Scale (PANSS) score Ն 60 received a 6-week treatment of antipsychotic medications randomly chosen from 5 atypical and 2 typical antipsychotic medications. Whole-exome sequencing (WES) was performed in 316 participants (grouped into those with the best response [n=156] and those who had no response [n=160] to the antipsychotic medication prescribed), according to the total PANSS score reduction rate after 6 weeks of treatment. Validation was performed using targeted sequencing in an independent sample of 1920 patients. Data analyses was performed between March 15, 2016, and March 1, 2017. MAIN OUTCOMES AND MEASURES Drug efficacy at week 6 was assessed according to the change in PANSS scores from baseline. Extremely good and extremely poor responders were selected for an initial WES association study, from which a subset of genes showing putative association was selected for independent replication with a targeted sequencing approach. RESULTS Of the 3023 patients (1549 [51.24%] female and 1474 [48.8%] male; mean [SD] age, 31.2 [7.9] years), 2336 (77.3%) were eligible for genetic analysis. After quality-control exclusions, 316 patients (10.5%) were included for WES and 1920 (63.5%) were included for replication. In the WES discovery stage, 2 gene sets (reduced NMDA [N-methyl-D-aspartate]mediated synaptic currents and reduced AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid]-mediated synaptic currents) were found to be enriched with rare damaging variants in the nonresponder group, suggesting the involvement of these gene sets in antipsychotic medication efficacy. Reduced NMDA-mediated synaptic currents gene set was further replicated in an independent sample using targeting sequencing. No statistically significant differences in antipsychotic drug response were found among the patients who received different antipsychotic drugs. CONCLUSIONS AND RELEVANCE Genetic variation in glutamatergic or NMDA neurotransmission is implicated in short-term antipsychotic medication efficacy; WES may have utility in the study of rare genetic variation in pharmacogenetics.

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