Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism.

BACKGROUND: X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS. OBJECTIVE: This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs. METHODS: Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF). RESULTS: When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (ß = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]). CONCLUSIONS: Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

ANO10-Related Spinocerebellar Ataxia: MDSGene Systematic Literature Review and a Romani Case Series.

BACKGROUND: Biallelic pathogenic variants in the ANO10 gene cause autosomal recessive progressive ataxia (ATX-ANO10). METHODS: Following the MDSGene protocol, we systematically investigated genotype-phenotype relationships in ATX-ANO10 based on the clinical and genetic data from 82 published and 12 newly identified patients. RESULTS: Most patients (>80%) had loss-of-function (LOF) variants. The most common variant was c.1150_1151del, found in all 29 patients of Romani ancestry, who had a 14-year earlier mean age at onset than patients homozygous for other LOF variants. We identified previously undescribed clinical features of ATX-ANO10 (e.g., facial muscle involvement and strabismus) suggesting the involvement of brainstem pathology, and we propose a diagnostic algorithm that may aid clinical ATX-ANO10 diagnosis. CONCLUSIONS: The early disease onset in patients with c.1150_1151del may indicate the existence of genetic/environmental disease-modifying factors in the Romani population. Our findings will inform patient counseling and may improve our understanding of the disease mechanism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Reversible intracranial contrast medium accumulation after embolization of unruptured cerebral aneurysms and its association with transient neurological deficits: A single center experience.

BACKGROUND: Use of iodine-containing contrast medium (CM) is obligatory for endovascular treatment (EVT) of cerebral aneurysms. After EVT, intracranial density increases (DIs) can be detected in cranial computed tomography (CT). Those DI can correspond to subarachnoid hemorrhage (SAH), infarction or reversible CM accumulation (RCMA). The latter can be mistaken for hemorrhage, especially if they are accompanied by neurological deficits. OBJECTIVE: To analyze postinterventional DI after EVT of unruptured cerebral aneurysms and associated clinical symptoms and to identify risk factors for the occurrence of RCMA. METHODS: For differentiation of DI, we compared CT scans following EVT and additionally 24 h ± 5 h later. Diagnosis of RCMA was based on marked regression of DI on follow-up scans. We analyzed continuous variables (age, duration of intervention and anesthesia, aneurysm diameter, amount of CM and renal function) and categorial variables (gender, aneurysm location, devices for EVT, antiplatelet therapy [APT] and associated neurological deficits) to identify risk factors for the occurrence of RCMA. RESULTS: We studied 58 patients (44 female, mean age 59.5 [range 39-81]) who underwent EVT for a total of 68 cerebral aneurysms in 62 therapy sessions over a 3-year period without periprocedural complications. Postinterventional DI occurred after 17 therapy sessions. All 17 DI turned out to be RCMA in the follow-up imaging. Two patients who had no DI on initial postinterventional CT showed new SAH on follow-up CT. Infarctions were not observed. Transient neurological deficits occurred in eight patients (12.9%) and were associated with RCMA (P = 0.010). Postinterventional RCMA was associated with the duration of EVT (P = 0.038) and with APT (acetylsalicylic acid [ASA] + clopidogrel: P =0.040; ASA alone: P =0.011). CONCLUSIONS: RCMA is common after EVT of unruptured cerebral aneurysms and often accompanied by transient neurological deficits. Long procedure duration and APT appear to predispose to the occurrence of RCMA.

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism.

BACKGROUND: A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk. OBJECTIVE: To investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic PD (iPD). METHODS: We included N = 486 patients with LRRK2-PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP-PD), Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD-RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO. RESULTS: Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10-8 ). We observed that higher MGS was significantly associated with earlier AAO in LRRK2-PD (P = 0.047, ß = -1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, ß = 0.22). There was a correlation between MGS and AAO in LRRK2-PD patients of European descent (P = 0.049, r = -0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = -0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, ß = -5.65) in LRRK2-PD and with tobacco use (P = 0.010, ß = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non-smokers. CONCLUSIONS: The MGS was more strongly associated with earlier AAO in LRRK2-PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Basal Ganglia Atrophy as a Marker for Prodromal X-Linked Dystonia-Parkinsonism.

In neurodegenerative diseases, the characterization of the prodromal phase is essential for the future application of disease-modifying therapies. X-linked dystonia-parkinsonism is a hereditary neurodegenerative movement disorder characterized by severe adult-onset dystonia accompanied by parkinsonism. Distinct striatal and pallidal atrophy is present already in early disease stages indicating a long-lasting presymptomatic degenerative process. To gain insight into the prodromal phase of X-linked dystonia-parkinsonism, structural and iron-sensitive magnetic resonance imaging (MRI) was performed in 10 non-manifesting carriers and 24 healthy controls in a double-blind fashion. Seventeen patients with X-linked dystonia-parkinsonism were recruited to replicate previous findings of basal ganglia pathology and iron accumulation. Age at onset was estimated in non-manifesting carriers and patients using the repeat length of the hexanucleotide expansion and 3 single-nucleotide polymorphisms associated with age at onset. Voxel-based morphometry and subcortical volumetry showed striatal and pallidal atrophy in non-manifesting carriers (~10%) and patients (~40%). Substantia nigra volume was similarly reduced in patients (~40%). Caudate volume correlated with time to estimated onset in non-manifesting carriers. Susceptibility-weighted imaging confirmed iron deposition in the anteromedial putamen in patients. Non-manifesting carriers also showed small clusters of iron accumulation in the same area after lowering the statistical threshold. In conclusion, basal ganglia atrophy and iron accumulation precede the clinical onset of X-linked dystonia-parkinsonism and can be detected years before the estimated disease manifestation. It thereby highlights the potential of multimodal imaging to identify clinically unaffected mutation carriers with incipient neurodegeneration and to monitor disease progression independent of clinical measures. Longitudinal studies are needed to further elucidate the onset and progression rate of neurodegeneration in prodromal X-linked dystonia-parkinsonism. ANN NEUROL 2023;93:999-1011.

Mosaic divergent repeat interruptions in XDP influence repeat stability and disease onset.

While many genetic causes of movement disorders have been identified, modifiers of disease expression are largely unknown. X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a SINE-VNTR-Alu(AGAGGG)n retrotransposon insertion in TAF1, with a polymorphic (AGAGGG)n repeat. Repeat length and variants in MSH3 and PMS2 explain ∼65% of the variance in age at onset (AAO) in XDP. However, additional genetic modifiers are conceivably at play in XDP, such as repeat interruptions. Long-read nanopore sequencing of PCR amplicons from XDP patients (n = 202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment confirmed the presence of identified divergent repeat motifs. In addition to the canonical pure SINE-VNTR-Alu-5'-(AGAGGG)n, we observed a mosaic of divergent repeat motifs that polarized at the beginning of the tract, where the divergent repeat interruptions varied in motif length by having one, two, or three nucleotides fewer than the hexameric motif, distinct from interruptions in other disease-associated repeats, which match the lengths of the canonical motifs. All divergent configurations occurred mosaically and in two investigated brain regions (basal ganglia, cerebellum) and in blood-derived DNA from the same patient. The most common divergent interruption was AGG [5'-SINE-VNTR-Alu(AGAGGG)2AGG(AGAGGG)n], similar to the pure tract, followed by AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n], at median frequencies of 0.425 (IQR: 0.42-0.43) and 0.128 (IQR: 0.12-0.13), respectively. The mosaic AGG motif was not associated with repeat number (estimate = -3.8342, P = 0.869). The mosaic pure tract frequency was associated with repeat number (estimate = 45.32, P = 0.0441) but not AAO (estimate = -41.486, P = 0.378). Importantly, the mosaic frequency of the AGGG negatively correlated with repeat number after adjusting for age at sampling (estimate = -161.09, P = 3.44 × 10-5). When including the XDP-relevant MSH3/PMS2 modifier single nucleotide polymorphisms into the model, the mosaic AGGG frequency was associated with AAO (estimate = 155.1063, P = 0.047); however, the association dissipated after including the repeat number (estimate = -92.46430, P = 0.079). We reveal novel mosaic divergent repeat interruptions affecting both motif length and sequence (DRILS) of the canonical motif polarized within the SINE-VNTR-Alu(AGAGGG)n repeat. Our study illustrates: (i) the importance of somatic mosaic genotypes; (ii) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; and (iii) that these variations may remain undetected without assessment of single molecules.

Causal Effect of Age at Menarche on the Risk for Depression: Results From a Two-Sample Multivariable Mendelian Randomization Study.

A fair number of epidemiological studies suggest that age at menarche (AAM) is associated with depression, but the reported effect sizes are small, and there is evidence of residual confounding. Moreover, previous Mendelian randomization (MR) studies to avoid inferential problems inherent to epidemiological studies have provided mixed findings. To clarify the causal relationship between age at menarche and broadly defined depression risk, we used 360 genome-wide significantly AAM-related single-nucleotide polymorphisms (SNPs) as instrumental variable and data from the latest GWAS for the broadly defined depression risk on 807,553 individuals (246,363 cases and 561,190 controls). Multiple methods to account for heterogeneity of the instrumental variable (penalized weighted median, MR Lasso, and contamination mixture method), systematic and idiosyncratic pleiotropy (MR RAPS), and horizontal pleiotropy (MR PRESSO and multivariable MR using three methods) were used. Body mass index, education attainment, and total white blood count were considered pleiotropic phenotypes in the multivariable MR analysis. In the univariable [inverse-variance weighted (IVW): OR = 0.96, 95% confidence interval = 0.94-0.98, p = 0.0003] and multivariable MR analysis (IVW: OR = 0.96, 95% confidence interval = 0.94-0.99, p = 0.007), there was a significant causal effect of AAM on depression risk. Thus, the present study supports conclusions from previous epidemiological studies implicating AAM in depression without the pitfalls of residual confounding and reverse causation. Considering the adverse consequences of an earlier AAM on mental health, this finding should foster efforts to address risk factors that promote an earlier AAM.

Prodromal X-Linked Dystonia-Parkinsonism is Characterized by a Subclinical Motor Phenotype.

BACKGROUND: Early diagnosis in patients with neurodegenerative disorders is crucial to initiate disease-modifying therapies at a time point where progressive neurodegeneration can still be modified. OBJECTIVES: The objective of this study was to determine whether motor or non-motor signs of the disease occur as indicators of a prodromal phase of X-linked dystonia-parkinsonism (XDP), a highly-penetrant monogenic movement disorder with striking basal ganglia pathology. METHODS: In addition to a comprehensive clinical assessment, sensor-based balance and gait analyses were performed in non-manifesting mutation carriers (NMCs), healthy controls (HCs), and patients with XDP. Gradient-boosted trees (GBT) methodology was utilized to classify groups of interest. RESULTS: There were no clinically overt disease manifestations in the NMCs. Balance analysis, however, revealed a classification accuracy of 90% for the comparison of NMC versus HC. For the gait analysis, the best-performing GBT-based model showed a balanced accuracy of 95% (NMC vs. HC; walking at maximum speed). Using a separate analysis of genetic modifiers, several gait parameters correlated strongly with the estimated age at disease onset in the NMC group. CONCLUSIONS: Our study unraveled balance and gait abnormalities in NMCs that preceded the onset of XDP. These findings demonstrate prodromal motor changes among NMCs who will develop XDP with a very high likelihood in the future. Gait abnormalities had a predictive value for the estimated age at onset highlighting the impact of genetic modifiers in personalized treatment in monogenic neurodegenerative disorders. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Validity and Prognostic Value of a Polygenic Risk Score for Parkinson's Disease.

Idiopathic Parkinson's disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible.

Suggestive Evidence for Causal Effect of Leptin Levels on Risk for Anorexia Nervosa: Results of a Mendelian Randomization Study.

Genetic correlations suggest a coexisting genetic predisposition to both low leptin levels and risk for anorexia nervosa (AN). To investigate the causality and direction of these associations, we performed bidirectional two-sample Mendelian randomization (MR) analyses using data of the most recent genome-wide association study (GWAS) for AN and both a GWAS and an exome-wide-association-study (EWAS) for leptin levels. Most MR methods with genetic instruments from GWAS showed a causal effect of lower leptin levels on higher risk of AN (e.g. IVW b = -0.923, p = 1.5 × 10-4). Because most patients with AN are female, we additionally performed analyses using leptin GWAS data of females only. Again, there was a significant effect of leptin levels on the risk of AN (e.g. IVW b = -0.826, p = 1.1 × 10-04). MR with genetic instruments from EWAS showed no overall effect of leptin levels on the risk for AN. For the opposite direction, MR revealed no causal effect of AN on leptin levels. If our results are confirmed in extended GWAS data sets, a low endogenous leptin synthesis represents a risk factor for developing AN.

Genotype-Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review.

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal-dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype-phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Brain Regional Differences in Hexanucleotide Repeat Length in X-Linked Dystonia-Parkinsonism Using Nanopore Sequencing.

OBJECTIVE: Our study investigated the presence of regional differences in hexanucleotide repeat number in postmortem brain tissues of 2 patients with X-linked dystonia-parkinsonism (XDP), a combined dystonia-parkinsonism syndrome modified by a (CCCTCT)n repeat within the causal SINE-VNTR-Alu retrotransposon insertion in the TAF1 gene. METHODS: Genomic DNA was extracted from blood and postmortem brain samples, including the basal ganglia and cortex from both patients and from the cerebellum, midbrain, and pituitary gland from 1 patient. Repeat sizing was performed using fragment analysis, small-pool PCR-based Southern blotting, and Oxford nanopore sequencing. RESULTS: The basal ganglia (p < 0.001) and cerebellum (p < 0.001) showed higher median repeat numbers and higher degrees of repeat instability compared with blood. CONCLUSIONS: Somatic repeat instability may predominate in brain regions selectively affected in XDP, thereby hinting at its potential role in disease manifestation and modification.

Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism.

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10-8). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington's disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.

A mendelian randomization study on causal effects of 25(OH)vitamin D levels on attention deficit/hyperactivity disorder.

BACKGROUND: While observational studies revealed an inverse association between serum 25(OH)vitamin D (25(OH)D) and the risk of attention deficit/hyperactivity disorder (ADHD), the causality of this relationship remains unclear. METHODS: We conducted a bidirectional two-sample Mendelian Randomization (MR) study to examine whether 25(OH)D has an effect on the risk to develop ADHD or vice versa. Information on single nucleotide polymorphisms (SNP) associated with serum 25(OH)D was obtained from a genome-wide association study (GWAS) considering phenotype data from 79,366 individuals of European ancestry. Data on risk for ADHD were derived from a GWAS analysis with 20,183 individuals diagnosed with ADHD and 35,191 controls. For our analysis, we considered effect sizes based on the European participants (19,099 cases and 34,194 controls). RESULTS: Single SNP analyses showed a causal effect of vitamin D on ADHD risk for only one SNP (rs12785878, p = 0.024). The overall MR estimates did not reveal a causal effect of 25(OH)D on risk for ADHD. In the reverse analysis, neither any single nor the multi-SNP MR analyses showed a causal effect of ADHD on 25(OH)D. CONCLUSION: Results from this two-sample MR study did not confirm a causal effect of 25(OH)D on ADHD or vice versa. Accordingly, our study does not provide evidence that improving 25(OH)D via supplementation could reduce the risk of developing ADHD.

DNA Methylation as a Potential Molecular Mechanism in X-linked Dystonia-Parkinsonism.

BACKGROUND: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder. The underlying molecular basis has still not been completely elucidated, but likely involves dysregulation of TAF1 expression. In X-linked dystonia-parkinsonism, 3 disease-specific single-nucleotide changes (DSCs) introduce (DSC12) or abolish (DSC2 and DSC3) CpG dinucleotides and consequently sites of putative DNA methylation. Because transcriptional regulation tightly correlates with specific epigenetic marks, we investigated the role of DNA methylation in the pathogenesis of X-linked dystonia-parkinsonism. METHODS: DNA methylation at DSC12, DSC3, and DSC2 was quantified by bisulfite pyrosequencing in DNA from peripheral blood leukocytes, fibroblasts, induced pluripotent stem cell-derived cortical neurons and brain tissue from X-linked dystonia-parkinsonism patients and age- and sex-matched healthy Filipino controls in a prospective study. RESULTS: Compared with controls, X-linked dystonia-parkinsonism patients showed striking differences in DNA methylation at the 3 investigated CpG sites. Using methylation-sensitive luciferase reporter gene assays and immunoprecipitation, we demonstrated (1) that lack of DNA methylation because of DSC2 and DSC3 affects gene promoter activity and (2) that methylation at all 3 investigated CpG sites alters DNA-protein interaction. Interestingly, DSC3 decreased promoter activity per se compared with wild type, and promoter activity further decreased when methylation was present. Moreover, we identified specific binding of proteins to the investigated DSCs that are associated with splicing and RNA and DNA binding. CONCLUSIONS: We identified altered DNA methylation in X-linked dystonia-parkinsonism patients as a possible additional mechanism modulating TAF1 expression and putative novel targets for future therapies using DNA methylation-modifying agents. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study.

Anthropometric traits and mental disorders or traits are known to be associated clinically and to show genetic overlap. We aimed to identify genetic variants with relevance for mental disorders/traits and either (i) body mass index (or obesity), (ii) body composition, (and/or) (iii) body fat distribution. We performed a look-up analysis of 1,005 genome-wide significant SNPs for BMI, body composition, and body fat distribution in 15 mental disorders/traits. We identified 40 independent loci with one or more SNPs fulfilling our threshold significance criterion (P < 4.98 × 10-5) for the mental phenotypes. The majority of loci was associated with schizophrenia, educational attainment, and/or intelligence. Fewer associations were found for bipolar disorder, neuroticism, attention deficit/hyperactivity disorder, major depressive disorder, depressive symptoms, and well-being. Unique associations with measures of body fat distribution adjusted for BMI were identified at five loci only. To investigate the potential causality between body fat distribution and schizophrenia, we performed two-sample Mendelian randomization analyses. We found no causal effect of body fat distribution on schizophrenia and vice versa. In conclusion, we identified 40 loci which may contribute to genetic overlaps between mental disorders/traits and BMI and/or shape related phenotypes. The majority of loci identified for body composition overlapped with BMI loci, thus suggesting pleiotropic effects.

Vitamin D and the Risk of Depression: A Causal Relationship? Findings from a Mendelian Randomization Study.

While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., "depressive symptoms" (DS, n = 161,460) and "broad depression" (BD, n = 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all p > 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038, p = 0.52) or on BD (IVW; b = 0.020, SE = 0.012, p = 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

A hexanucleotide repeat modifies expressivity of X-linked dystonia parkinsonism.

OBJECTIVE: X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT)n repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP. METHODS: We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients. RESULTS: RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain. INTERPRETATION: The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.