GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

Background: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA) expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA) and (GAA) expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine.

Methods: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial.

RFC1 repeat expansions in downbeat nystagmus syndromes: frequency and phenotypic profile.

Objectives: The cause of downbeat nystagmus (DBN) remains unknown in a substantial number of patients ("idiopathic"), although intronic GAA expansions in FGF14 have recently been shown to account for almost 50% of yet idiopathic cases. Here, we hypothesized that biallelic RFC1 expansions may also represent a recurrent cause of DBN syndrome.

Methods: We genotyped the RFC1 repeat and performed in-depth phenotyping in 203 patients with DBN, including 65 patients with idiopathic DBN, 102 patients carrying an FGF14 GAA expansion, and 36 patients with presumed secondary DBN.

Role of the repeat expansion size in predicting age of onset and severity in RFC1 disease.

RFC1 disease, caused by biallelic repeat expansion in RFC1, is clinically heterogeneous in terms of age of onset, disease progression and phenotype. We investigated the role of the repeat size in influencing clinical variables in RFC1 disease. We also assessed the presence and role of meiotic and somatic instability of the repeat.

Frequency and Phenotype of Repeat Expansions in Bilateral Vestibulopathy.

Background And Objectives: Bilateral vestibulopathy (BVP) is a chronic debilitating neurologic disorder with no monogenic cause established so far despite familiar presentations. We hypothesized that replication factor complex subunit 1 (RFC1) repeat expansions might present a recurrent monogenic cause of BVP.

Methods: The study involved RFC1 screening and in-depth neurologic, vestibulo-oculomotor, and disease evolution phenotyping of 168 consecutive patients with idiopathic at least "probable BVP" from a tertiary referral center for balance disorders, with127 of them meeting current diagnostic criteria of BVP (Bárány Society Classification).

Impact of genetic variants within serotonin turnover enzymes on human cerebral monoamine oxidase A in vivo.

Variants within the monoamine oxidase A (MAO-A, MAOA) and tryptophan hydroxylase 2 (TPH2) genes, the main enzymes in cerebral serotonin (5-HT) turnover, affect risk for depression. Depressed cohorts show increased cerebral MAO-A in positron emission tomography (PET) studies. TPH2 polymorphisms might also influence brain MAO-A because availability of substrates (i.

Schizophrenia risk conferred by rare protein-truncating variants is conserved across diverse human populations.

Schizophrenia (SCZ) is a chronic mental illness and among the most debilitating conditions encountered in medical practice. A recent landmark SCZ study of the protein-coding regions of the genome identified a causal role for ten genes and a concentration of rare variant signals in evolutionarily constrained genes. This recent study-and most other large-scale human genetics studies-was mainly composed of individuals of European (EUR) ancestry, and the generalizability of the findings in non-EUR populations remains unclear.

Effect of MAOA DNA Methylation on Human in Vivo Protein Expression Measured by [11C]harmine Positron Emission Tomography.

Background: Epigenetic modifications like DNA methylation are understood as an intermediary between environmental factors and neurobiology. Cerebral monoamine oxidase A (MAO-A) levels are altered in depression, as are DNA methylation levels within the MAOA gene, particularly in the promoter/exon I/intron I region. An effect of MAOA methylation on peripheral protein expression was shown, but the extent to which methylation affects brain MAO-A levels is not fully understood.

Uncovering the genetic architecture of broad antisocial behavior through a genome-wide association study meta-analysis.

Despite the substantial heritability of antisocial behavior (ASB), specific genetic variants robustly associated with the trait have not been identified. The present study by the Broad Antisocial Behavior Consortium (BroadABC) meta-analyzed data from 28 discovery samples (N = 85,359) and five independent replication samples (N = 8058) with genotypic data and broad measures of ASB. We identified the first significant genetic associations with broad ASB, involving common intronic variants in the forkhead box protein P2 (FOXP2) gene (lead SNP rs12536335, p = 6.

ABCB1 variants and sex affect serotonin transporter occupancy in the brain.

Strategies to personalize psychopharmacological treatment promise to improve efficacy and tolerability. We measured serotonin transporter occupancy immediately after infusion of the widely prescribed P-glycoprotein substrate citalopram and assessed to what extent variants of the ABCB1 gene affect drug target engagement in the brain in vivo. A total of 79 participants (39 female) including 31 patients with major depression and 48 healthy volunteers underwent two PET/MRI scans with the tracer [C]DASB and placebo-controlled infusion of citalopram (8 mg) in a cross-over design.

Borderline personality disorder and the big five: molecular genetic analyses indicate shared genetic architecture with neuroticism and openness.

Both environmental (e.g. interpersonal traumatization during childhood and adolescence) and genetic factors may contribute to the development of Borderline Personality Disorder (BPD).

New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis.

A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo.

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (N = 48,072, N = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo.

Aβ misfolding in blood plasma is inversely associated with body mass index even in middle adulthood.

Background: To understand the potential for early intervention and prevention measures in Alzheimer's disease, the association between risk factors and early pathological change needs to be assessed. Hence, the aim of this study was to determine whether risk factors of Alzheimer's clinical syndrome (clinical AD), such as body mass index (BMI), are associated with Aβ misfolding in blood, a strong risk marker for AD among older adults.

Methods: Information on risk factors and blood samples were collected at baseline in the ESTHER study, a population-based cohort study of older adults (age 50-75 years) in Germany.

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene).

Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders.

Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.

Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets.

Genetic predisposition, Aβ misfolding in blood plasma, and Alzheimer's disease.

Alzheimer's disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, Aβ misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer's disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer's disease and Aβ based) were calculated, APOE genotype was determined, and Aβ misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer's disease during 14 years of follow-up and 581 participants without dementia diagnosis.

HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry.

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors.

Aβ misfolding in blood plasma measured by immuno-infrared-sensor as an age-independent risk marker of Alzheimer's disease.

Introduction: Determining potential risk factors of amyloid beta (Aβ) misfolding in blood, a risk marker for clinical Alzheimer's disease (AD), could have important implications for its utility in future research and clinical settings.

Methods: Participants aged 50 to 75 years attending a general health examination were recruited for a prospective community-based cohort study in Saarland, Germany, in 2000 to 2002. For these analyses, participants with available Aβ misfolding measurements and clinical AD information at 17-year follow-up were included ( = 444).