Genome-Wide Association Study of Chronic Dizziness in the Elderly Identifies Loci Implicating MLLT10, BPTF, LINC01224, and ROS1.

PURPOSE: Chronic age-related imbalance is a common cause of falls and subsequent death in the elderly and can arise from dysfunction of the vestibular system, an elegant neuroanatomical group of pathways that mediates human perception of acceleration, gravity, and angular head motion. Studies indicate that 27-46% of the risk of age-related chronic imbalance is genetic; nevertheless, the underlying genes remain unknown. METHODS: The cohort consisted of 50,339 cases and 366,900 controls in the Million Veteran Program. The phenotype comprised cases with two ICD diagnoses of vertigo or dizziness at least 6 months apart, excluding acute or recurrent vertiginous syndromes and other non-vestibular disorders. Genome-wide association studies were performed as individual logistic regressions on European, African American, and Hispanic ancestries followed by trans-ancestry meta-analysis. Downstream analysis included case-case-GWAS, fine mapping, probabilistic colocalization of significant variants and genes with eQTLs, and functional analysis of significant hits. RESULTS: Two significant loci were identified in Europeans, another in the Hispanic population, and two additional in trans-ancestry meta-analysis, including three novel loci. Fine mapping revealed credible sets of intronic single nucleotide polymorphisms (SNPs) in MLLT10 - a histone methyl transferase cofactor, BPTF - a subunit of a nucleosome remodeling complex implicated in neurodevelopment, and LINC01224 - a proto-oncogene receptor tyrosine kinase. CONCLUSION: Despite the difficulties of phenotyping the nature of chronic imbalance, we replicated two loci from previous vertigo GWAS studies and identified three novel loci. Findings suggest candidates for further study and ultimate treatment of this common elderly disorder.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

The functional roles of IGF-1 variants in the susceptibility and clinical outcomes of mild traumatic brain injury.

BACKGROUND: Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. This study attempted to elucidate the effects of IGF-1 variants on the risk and neuropsychiatric outcomes of mTBI. METHODS: Based on 176 recruited mTBI patients and 1517 control subjects from the Taiwan Biobank project, we first compared the genotypic distributions of IGF-1 variants between the two groups. Then, we analyzed associations of IGF-1 variants with neuropsychiatric symptoms after mTBI, including anxiety, depression, dizziness, and sleep disturbances. Functional annotation of IGF-1 variants was also performed through bioinformatics databases. RESULTS: The minor allele of rs7136446 was over-represented in mTBI patients compared to community-based control subjects. Patients carrying minor alleles of rs7136446 and rs972936 showed more dizziness and multiple neuropsychiatric symptoms after brain injury. CONCLUSIONS: IGF-1 variants were associated with the risk and neuropsychiatric symptoms of mTBI. The findings highlight the important role of IGF-1 in the susceptibility and clinical outcomes of mTBI.

[Genetics research on vestibular migraine].

The combination of vertigo, dizziness and balance disturbance with migraine is called vestibular migraine, which is frequently reported in clinical neurology. However, the exact pathophysiological mechanisms of vestibular migraine still remain unclear. Familial occurrence of VM has been reported, suggesting a genetic component. With the rapid development of molecular genetic technology in recent decades, the genetic research about vestibular migraine has become a hot topic. The outcomes of molecular genetic studies of vestibular migraine could benefit to unveil the mysterious causes of this disorder. The present review summarized the molecular genetic studies of vestibular migraine.

Association between dopamine receptor D2 Taq IA gene polymorphism and persistent postural-perceptual dizziness.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is a chronic dizziness, its pathogenesis is unknown by now. OBJECTIVE: To study the relationship between the DRD2 gene TaqIA polymorphisms and PPPD, and further to explore the molecular mechanism underlying this disease. METHODS: 43 patients diagnosed with PPPD and 45 randomly selected cases (matched by age and sex) were included in the study and control group, respectively. DRD2 gene TaqIA polymorphisms were detected in all participants by polymerase chain reaction (PCR)combined with the restriction fragment length polymorphism (RFLP) method. RESULTS: In the study group, frequencies of the A1 and A2 TaqIA alleles (65.1% and 34.9%, respectively) were significantly different to those in the control group (46.7% and 53.3%, respectively; P < 0.05). The allele frequency in the study group for the A1/A1 genotype was 34.9%, for A1/A2 was 60.5%, and for A2/A2 was 4.6%, all of which were significantly higher than the control group (24.4%, 44.5%. and 31.1%, respectively; P < 0.01). CONCLUSIONS: Our findings indicate that the DRD2 TaqIA A1 allele is possibly the susceptibility polymorphism for PPPD, and that the A2/A2 genotype has a potentially protective role for PPPD. However, larger independent studies are required for further validation.

Hereditary Angioedema Type 1 with Recurrent Dizziness.

A 41-year-old woman presented with recurrent dizziness. After an attack of dizziness, she felt edematous sensations in her hands. However, according to photographs taken during the attack, the edema on the back of the patient's hands and fingers appeared mild. Laboratory examinations revealed a low C4 and C1 inhibitor (INH) activity. A direct sequencing analysis of C1INH revealed a pathogenic gene mutation. Based on these results, she was diagnosed with hereditary angioedema (HAE) type 1. These findings indicate that HAE can cause recurrent dizziness, and it should therefore be included in the differential diagnosis in patients with recurrent neurologic symptoms, even in the absence of severe edema.

Impact of UGT1A1 gene polymorphisms on plasma dolutegravir trough concentrations and neuropsychiatric adverse events in Japanese individuals infected with HIV-1.

BACKGROUND: Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated. METHODS: The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs. RESULTS: The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 µg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 µg/mL) than in those without NP-AEs (1.01 µg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454). CONCLUSION: In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs.

A marked decrease in heart rate variability in Marfan syndrome patients with confirmed FBN1 mutations.

BACKGROUND: The studies on heart rate variability (HRV), a key predictor of all-cause mortality, in Marfan syndrome (MS), up to now have not been reported, especially in patients with FBN1 mutations. METHODS: Among 18 MS patients with the phenotype of MS meeting inclusion criteria 15 have had a FBN1 gene mutation. Short electrocardiography records were taken in the supine position and during orthostatic tests. The control group consisted of 30 apparently healthy nonathletes matched by age and gender. RESULTS: Heart rates in MS patients with the FBN1 mutation were increased in both the supine position and orthostatic test (p < 0.001). Most of the time-domain (standard deviation, pNN50) and frequency-domain (total power, very low, low, and high frequency) parameters of HRV were significantly reduced in the MS patients (p < 0.001). CONCLUSIONS: A marked decrease in HRV, documented in the study, may be an important clinical feature in MS patients with confirmed FBN1 gene mutations.

Novel mutation in GRXCR1 at DFNB25 lead to progressive hearing loss and dizziness.

OBJECTIVE: We identified 2 patients in 1 family who had novel mutations in GRXCR1, which caused progressive hearing loss. METHODS: One thousand one hundred twenty Japanese hearing loss patients with sensorineural hearing loss from unrelated families were enrolled in this study. Targeted genomic enrichment with massively parallel sequencing of all known nonsyndromic hearing loss genes was used to identify the genetic causes of hearing loss. RESULTS: In this study, 2 affected individuals with compound heterozygous mutations-c.439C>T (p.R147C) and c.784C>T (p.R262X)-in GRXCR1 were identified. The proband had moderate to severe hearing loss and suffered from dizziness with bilateral canal paralysis. CONCLUSION: Our cases are the first identified in the Japanese population and are consistent with previously reported cases. The frequency of mutations in GRXCR1 seems to be extremely rare. This study underscores the importance of using comprehensive genetic testing for hearing loss. Furthermore, longitudinal audiologic assessment and precise vestibular testing are necessary for a better understanding of the mechanisms of hearing loss and vestibular dysfunction caused by GRXCR1 mutations.

The influence of BMX gene polymorphisms on clinical symptoms after mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is one of the most common neurological disorders. Most patients diagnosed with mTBI could fully recover, but 15% of patients suffer from persistent symptoms. In recent studies, genetic factors were found to be associated with recovery and clinical outcomes after TBI. In addition, results from our previous research have demonstrated that the bone marrow tyrosine kinase gene in chromosome X (BMX), a member of the Tec family of kinases, is highly expressed in rats with TBI. Therefore, our aim in this study was to identify the association between genetic polymorphisms of BMX and clinical symptoms following mTBI. Four tagging single nucleotide polymorphisms (tSNPs) of BMX with minimum allele frequency (MAF) >1% were selected from the HapMap Han Chinese database. Among these polymorphisms, rs16979956 was found to be associated with the Beck anxiety inventory (BAI) and dizziness handicap inventory (DHI) scores within the first week after head injury. Additionally, another SNP, rs35697037, showed a significant correlation with dizziness symptoms. These findings suggested that polymorphisms of the BMX gene could be a potential predictor of clinical symptoms following mTBI.

Orthostatic blood pressure dysregulation and polymorphisms of ß-adrenergic receptor genes in hypertensive patients.

The genetic susceptibility to orthostatic blood pressure dysregulation remains poorly understood. The association between polymorphisms of beta-adrenergic receptor (ß-AR) genes and orthostatic blood pressure dysregulation in hypertensive patients was investigated. Two polymorphisms of ß1 -AR (Arg389/Gly) and ß2 -AR (Arg16/Gly) were genotyped in untreated hypertensive patients and normotensive patients. In patients with untreated hypertension, the frequency of ß1 -AR Gly389 homozygote was significantly higher in patients with orthostatic hypotension (OH) (P<.0001) and lower in patients with orthostatic hypertension (OHT) (P=.002) as compared with patients with orthostatic normotension (ONT) even after Bonferroni correction. After analysis by sex and adjustment for conventional risk factors, the ß1 -AR Gly389 homozygote conferred about a 3-fold risk of OH and independently predicted a 6.5 mm Hg greater orthostatic SBP decrease (GG -8.9±13 mm Hg vs CC+CG -2.4±12 mm Hg, P<.001) only in female hypertensive patients. The association of ß2 -AR Arg16/Gly with OH was not significant after adjustment for conventional risk factors. In normotensive patients, no association was identified between these two polymorphisms and OHT or OH. These results indicated that the ß1 -AR Arg389/Gly polymorphism may be associated with increased risk of OH in female hypertensive patients.

The association between CHRN genetic variants and dizziness at first inhalation of cigarette smoke.

Numerous single nucleotide polymorphisms (SNPs) in multiple nicotinic receptor genes (CHRN) are associated with smoking. However few studies have examined the association between CHRN SNPs and subjective responses to smoking in adolescents which may relate to sustained smoking, such as dizziness at first inhalation. The objective of this study was to investigate the association between 61 SNPs in eight CHRN genes (CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNB2, CHRNB3, CHRNB4) and dizziness at first inhalation. Data were available from a longitudinal cohort investigation of 1293 students 12-13year-old at baseline. Students completed self-report questionnaires at school every 3months for 5years during secondary school, and a mailed questionnaire three years later. DNA extracted from blood or saliva was genotyped for 61 CHRN SNPs selected using a gene tagging approach. Associations were modeled using logistic regression controlling for sex, race and age at first cigarette. Complete data were available for 356 of 475 participants (75%) who initiated smoking. The minor alleles of three SNPs in CHRNA6 (rs7812298, rs2304297, rs7828365) were associated with a decreased probability of dizziness (OR(95% CI)=0.54 (0.36, 0.81), 0.59 (0.40, 0.86) and 0.58 (0.36, 0.95), respectively), while one SNP in each of three other genes (rs3743077 (CHRNA3), rs755204 (CHRNA4), rs7178176 (CHRNA7)) was associated with an increased probability of dizziness (OR(95% CI)=1.40 (1.02, 1.90), 1.85 (1.05, 3.27) and 1.51 (1.06, 2.15), respectively). Thus, several SNPs located in CHRN genes are associated with dizziness at first inhalation, a smoking initiation phenotype that may relate to sustained smoking.

Genetics of dizziness: cerebellar and vestibular disorders.

PURPOSE OF REVIEW: Recent advances in next generation sequencing techniques (NGS) are increasing the number of novel genes associated with cerebellar and vestibular disorders. We have summarized clinical and molecular genetics findings in neuro-otolology during the last 2 years. RECENT FINDINGS: Whole-exome and targeted sequencing have defined the genetic basis of dizziness including new genes causing ataxia: GBA2, TGM6, ANO10 and SYT14. Novel mutations in KCNA1 and CACNA1A genes are associated with episodic ataxia type 1 and type 2, respectively. Moreover, new variants in genes such as COCH, MYO7A and POU4F3 are associated with nonsyndromic deafness and vestibular dysfunction. Several susceptibility loci have been linked to familial vestibular migraine, suggesting genetic heterogeneity, but no specific gene has been identified. Finally, loci for complex and heterogeneous diseases such as bilateral vestibular hypofunction or familial Ménière disease have not been identified yet, despite their strong familial aggregation. SUMMARY: Cerebellar and vestibular disorders leading to dizziness or episodic vertigo may show overlapping clinical features. A deep phenotyping including a complete familial history is a key step in performing a reliable molecular genetic diagnosis using NGS. Personalized molecular medicine will be essential to understand disease mechanisms as well as to improve their diagnosis and treatment.

[Impact of genetic factors on severity of side effects of opioids in patients after major surgical interventions].

The rate of the opioids side effects (SE) occurrence, as well as their mutual connection with possible variants of a single-nucleotide polymorphism (SNP) of genes of a µ1-opioid receptor (OPRM1) 118A>G and catechol-O-methyltranspherase (COMT) 1947G>A were studied in patients after surgical interventions of large volumes in the first postoperative day the rate of the narcotic analgetics SE occurrence have constituted: nemesis--56%, vomiting--17%, dizziness--61%, cutaneous pruritis--17%. Occurrence of central SE of opioids may be caused by the SNP COMT 1947G>A genes: the sedation depth is two times more in the genes AA and GA carriers, in comparison with such in the gene GG carrier (p < 0.05). Gastrointestinal SE may be connected with genes SNP OPRM1 118A>G and COMT 1947G>A: the nemesis occurrence rate is more in the genes OPRM1 AG+GG, COMT GA and GG carriers (p < 0.05), vomiting--in 2,8 times more in the OPRM1 AG+GG genes carriers, than in the group OPRM1 AA (p < 0.05). The severity of cutaneous SE of opiates may be dependent on the variant of SNP COMT 1947G>A: in genotype GG the cutaneous pruritis rate is in 2.9 times more, than in the AA+GA group (p < 0.05).

Understanding Bartter syndrome and Gitelman syndrome.

BACKGROUND: We aim to review the clinical features of two renal tubular disorders characterized by sodium and potassium wasting: Bartter syndrome and Gitelman syndrome. DATA SOURCES: Selected key references concerning these syndromes were analyzed, together with a PubMed search of the literature from 2000 to 2011. RESULTS: The clinical features common to both conditions and those which are distinct to each syndrome were presented. The new findings on the genetics of the five types of Bartter syndrome and the discrete mutations in Gitelman syndrome were reviewed, together with the diagnostic workup and treatment for each condition. CONCLUSIONS: Patients with Bartter syndrome types 1, 2 and 4 present at a younger age than classic Bartter syndrome type 3. They present with symptoms, often quite severe in the neonatal period. Patients with classic Bartter syndrome type 3 present later in life and may be sporadically asymptomatic or mildly symptomatic. The severe, steady-state hypokalemia in Bartter syndrome and Gitelman syndrome may abruptly become life-threatening under certain aggravating conditions. Clinicians need to be cognizant of such renal tubular disorders, and promptly treat at-risk patients.

Dizziness and the genetic influences on subjective experiences to initial cigarette use.

AIM: To examine individual differences in positive and negative subjective experiences to initial cigarette use. DESIGN: Retrospective self-reports of initial subjective experiences were examined to estimate the genetic and environmental influences and the extent of their covariation across different effects. PARTICIPANTS: Data was drawn from 2482 young adult same-and opposite sex twins- and siblings participating in the National Longitudinal Study of Adolescent Health. MEASUREMENT: Subjective experiences were retrospectively collected using the Early Smoking Experience (ESE) questionnaire. FINDINGS: Positive experiences evidenced moderate heritable contributions (40%, 95% CI: 0.22 to 0.56), as did an overall hedonic measure (34%, 95% CI: 0.22 to 0.46) and dizziness (34%, 95% CI: 0.15 to 0.52). Negative experiences evidenced small heritable contributions (13%, 95% CI: 0.00 to 0.36). Individual specific environmental influences were strong and accounted for the remaining proportion of observed variation in these experiences. Multivariate genetic modeling identified a moderately heritable underlying factor (37%, 95% CI: 0.22 to 0.52) that influenced the covariation of diverse subjective experiences and loaded most heavily on dizziness. Positive experiences also evidence residual genetic influences that were uncorrelated with other subjective experiences. CONCLUSIONS: How a person experiences their initial few cigarettes is due to both heritable contributions and environmental experiences unique to the person. The covariation of diverse subjective experiences appears to be due to a heritable latent sensitivity to the chemicals contained in an average cigarette and is best indexed by dizziness.

[Chronic dizziness in a pain patient--pharmacogenomic identification of tramadol as cause]. / Chronischer Schwindel bei einem Schmerzpatienten--pharmakogenomische Identifizierung von Tramadol als Ursache.

This casuistic reports on a 59-year-old pain patient taking normal dosage Tramadol as analgetic drug, who suffered from chronic dizziness leading to immobilisation for more than 9 months. On admission to inpatient rehabilitation Tramadol was removed in exchange for morphine sulphate with the unexpected result of a prompt and lasting stop of dizziness. A molecular-genetic investigation showed a duplication in the CYP2D6 gene. This genetic situation caused a quick metabolizing-status for substances dependent on CYP2D6 like Tramadol, which is a prodrug. The quick metabolizing-status resulted in an increased rate of active Tramadol-metabolites which caused the chronic dizziness. Under morphine sulphate which is metabolized independently of CYP2D6, a sufficient analgetic outcome could be achieved. Dizziness did not appear in the patient any longer, and he could be mobilised during rehabilitation. Pharmacogenomic knowledge has helped develop a sustainable concept for rehabilitation of this seriously ill patient, and to put it into practise successfully.