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Variants within the gene cluster encoding α3, α5, and β4 nicotinic receptor subunits are major risk factors for substance dependence. The strongest impact on risk is associated with variation in the CHRNA5 gene, where at least two mechanisms are at work: amino acid variation and altered mRNA expression levels. The risk allele of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele. In populations of European ancestry, there are approximately 50 highly correlated variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and the adjacent PSMA4 gene region that are associated with CHRNA5 mRNA levels. It is not clear which of these variants contribute to the changes in CHRNA5 transcript level. Because populations of African ancestry have reduced linkage disequilibrium among variants spanning this gene cluster, eQTL mapping in subjects of African ancestry could potentially aid in defining the functional variants that affect CHRNA5 mRNA levels. We performed quantitative allele specific gene expression using frontal cortices derived from 49 subjects of African ancestry and 111 subjects of European ancestry. This method measures allele-specific transcript levels in the same individual, which eliminates other biological variation that occurs when comparing expression levels between different samples. This analysis confirmed that substance dependence associated variants have a direct cis-regulatory effect on CHRNA5 transcript levels in human frontal cortices of African and European ancestry and identified 10 highly correlated variants, located in a 9 kb region, that are potential functional variants modifying CHRNA5 mRNA expression levels.

Chio and colleagues present a new set of clinical suggestions for the genetic counselling and testing of patients diagnosed with amyotrophic lateral sclerosis (ALS).1 The paper provides sage, straightforward advice for neurologists faced with questions from patients or their relatives about their risk of developing this fatal neurodegenerative disease and the role of genetic testing in quantifying that risk. Key among their recommendations is that mutational screening be extended to include more recently discovered genes. Furthermore, genetic testing should be discussed with all patients diagnosed with ALS, regardless of their family history. In so doing, the authors highlight the growing awareness among both the medical community and patients as to the predictive power of modern genomics. Recent advances in our understanding of ALS genetics make these updated clinical suggestions particularly timely. The genetic aetiology of two …

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [OR] = 1.21; p = 4.41 × 10(-7)), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10(-7)), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10(-7)). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R(2)(partial) = 0.0061; p = 6.59 × 10(-8)) and rs803675 (R(2)(partial) = 0.0060; p = 6.96 × 10(-8)). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease.

We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U.S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for

Frontotemporal dementia (FTD) as an important clinical entity was rediscovered in Lund and Manchester in the early 1990s. Here we show that the large Lund pedigree with behavioral variant of frontotemporal dementia previously described with this disorder has an expansion in the recently described C9ORF72 locus on chromosome 9.

Objective: To describe a patient with a double pathogenetic mutation of C9ORF72 and TARDBP genes. Background Several genes have been found to be related to ALS; however, patients carrying two different pathogenetic genetic mutations have never been described. Design/Methods: We are performing a study of genetic determinants of familial ALS in Italy. All patients undergo mutational analysis for SOD1, FUS and TARDBP and OPTN . Repeat primer PCR to screen the presence of the hexanucleotide expansion in the first intron of C9ORF72 is performed. Results: The index case was a year-old man who at 43 developed bulbar-onset ALS with behavioural frontemporal dementia (FTD) occurring one year later. He deceased 34 months after the onset of ALS. He carried both a A382T missense mutation of the TARDBP gene and a hexanucleotide repeat expansion of C9ORF72 gene. His father, who also had a hexanucleotide repeat expansion of C9ORF72 gene, developed spinal onset ALS at 64, and behavioural FTD two years later. He deceased 78 months after the onset of ALS. His mother developed spinal onset ALS at 69 and a mild FTD six months later. She deceased at 73. She carried a A382T missense mutation of the TARDBP gene. The proband9s brother developed ALS at 33 and deceased 75 months after the onset of ALS, without cognitive impairment. No DNA is available of this patients. Conclusions: The proband had two mutations pathogenetic for ALS and FTD, one ( TARDBP ) transmitted from the maternal line, and the other ( C9ORF72 ) from the paternal line. He developed ALS with FTD at 43 years, much earlier than his parents, and had a more severe clinical course. The presence of two pathogenetic mutations in this patients indicates that multiple genetic factors should be considered in pathogenesis of ALS and are likely to modify the clinical course of the disease. Disclosure: Dr. Calvo has nothing to disclose. Dr. Borghero has nothing to disclose. Dr. Cannas has nothing to disclose. Dr. Marrosu has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Marrosu has received personal compensation in an editorial capacity for Neurological Sciences. Dr. Marrosu has received research support from Serono Foundation, Biogen Idec, Schering Italy, and Sanofi Aventis. Dr. Murru has nothing to disclose. Dr. Floris has nothing to disclose. Dr. Traynor has received personal compensation in an editorial capacity for the journal Neurology. Dr. Renton has nothing to disclose. Dr. Moglia has nothing to disclose. Dr. Canosa has nothing to disclose. Dr. Ilardi has nothing to disclose. Dr. Cammarosano has nothing to disclose. Dr. Brunetti has nothing to disclose. Dr. Ossola has nothing to disclose. Dr. Restagno has nothing to disclose. Dr. Chio has nothing to disclose.

Mutations in the valosin-containing protein gene ( VCP ) have been identified in neurological disorders (inclusion body myopathy—early Paget's disease of the bone—frontotemporal dementia and amyotrophic lateral sclerosis) and are thought to play a role in the clearance of abnormally folded proteins. Parkinsonism has been noted in kindreds with VCP mutations. Based on this, we hypothesized that mutations in VCP may also contribute to idiopathic Parkinson's disease (PD). We screened the coding region of the VCP gene in a large cohort of 768 late-onset PD cases (average age at onset, 70 years), both sporadic and with positive family history. We identified a number of rare single nucleotide changes, including a variant previously described to be pathogenic, but no clear disease-causing variants. We conclude that mutations in VCP are not a common cause for idiopathic PD.

A fundamental challenge in the post-genome era is to understand and annotate the consequences of genetic variation, particularly within the context of human tissues. We present a set of integrated experiments that investigate the effects of common genetic variability on DNA methylation and mRNA expression in four human brain regions each from 150 individuals (600 samples total). We find an abundance of genetic cis regulation of mRNA expression and show for the first time abundant quantitative trait loci for DNA CpG methylation across the genome. We show peak enrichment for cis expression QTLs to be approximately 68,000 bp away from individual transcription start sites; however, the peak enrichment for cis CpG methylation QTLs is located much closer, only 45 bp from the CpG site in question. We observe that the largest magnitude quantitative trait loci occur across distinct brain tissues. Our analyses reveal that CpG methylation quantitative trait loci are more likely to occur for CpG sites outside of islands. Lastly, we show that while we can observe individual QTLs that appear to affect both the level of a transcript and a physically close CpG methylation site, these are quite rare. We believe these data, which we have made publicly available, will provide a critical step toward understanding the biological effects of genetic variation., Author Summary In this paper, we describe a comprehensive assessment of the correlation between common genetic variability across the human genome, gene expression, and DNA methylation, within human brain. We studied the cerebellum, frontal cortex, temporal cortex, and pons regions of 150 individuals (600 tissue samples). In each tissue, we assessed 27,578 DNA methylation sites and the expression level of 22,184 genes. Our research shows that DNA methylation and RNA expression patterns differ between brain regions. Further, we show that DNA genotype is correlated with gene expression and DNA methylation, particularly when the genetic variation is close to the DNA methylation site or gene.

Background: We conducted a prospective, population-based study of ALS in the Republic of Ireland for the 3-year period 1995 to 1997. Methods: To ensure complete case ascertainment, multiple sources of information were used, including consultant neurologists, neurophysiologists, primary care physicians, and the Irish Motor Neuron Disease Association. The El Escorial diagnostic criteria for ALS were applied to all cases enrolled on the register and each patient was regularly followed up during his or her illness. Results: Between January 1, 1995, and December 31, 1997, 231 patients were diagnosed with possible, probable, or definite ALS, including 133 men (57.6%) and 98 women (42.4%). The average annual incidence rate was 2.1 per 100,000 person-years (95% CI, 1.8 to 2.4), and 2.8 per 100,000 person-years for the population older than 15 years (95% CI, 2.4 to 3.1). The incidence rate was higher for men, being 2.5 per 100,000 person-years (95% CI, 2.0 to 2.9), than for women, at 1.8 per 100,000 person-years (95% CI, 1.5 to 2.2), and increased with age for both sexes. The median age at onset was 64.2 years for men and 67.8 years for women. On December 31, 1996, the crude prevalence was 4.7 per 100,000 of the total population (95% CI, 4.0 to 5.5), and 6.2 per 100,000 for the population older than 15 years (95% CI, 5.3 to 7.1). Adjusting to the 1996 Irish population as standard, the incidence of ALS in Ireland during the 3-year study period is the third highest reported to date. Conclusions: There was a trend toward a higher incidence of ALS in the northwestern region of Ireland, although the numbers of cases involved were small and further study is required.

Expansion mutations in the C9orf72 gene may cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or mixtures of the two clinical phenotypes. Different imaging findings have been described for C9orf72-associated diseases in comparison with sporadic patients with the same phenotypes, but it is uncertain whether different phenotypes have a common genotype-associated imaging signature. To address this question, 27 unrelated C9orf72 expansion mutation carriers (C9 +) with varied phenotypes, 28 age-matched healthy controls and 22 patients with sporadic ALS (sALS) underwent 3T MRI scanning and clinical phenotyping. Measures of brain volumes and cortical thickness were extracted from T1 images. Compared to healthy controls and sALS patients, symptomatic C9 + subjects had greater ventricular volume loss and thalamic atrophy for age, with diffuse, patchy cortical thinning. Asymptomatic carriers did not differ from controls. C9 + ALS and ALS-FTD patients had less thinning of the motor cortex than sALS patients, but more thinning in extramotor regions, particularly in frontal and temporal lobes. C9 + ALS patients differed from sporadic ALS patients in the thickness of the superior frontal gyrus and lateral orbitofrontal cortex. Thickness of the precentral gyrus was weakly correlated with the revised ALS functional rating scale. Thickness of many cortical regions, including several frontal and temporal regions, was moderately correlated with letter fluency scores. Letter fluency scores were weakly correlated with ventricular and thalamic volume. To better understand how imaging findings are related to disease progression, nineteen C9 + subjects and 23 healthy controls were scanned approximately 6 months later. Ventricular volume increased in C9 + patients with FTD and ALS-FTD phenotypes and remained stable in asymptomatic C9 + subjects. We conclude that diffuse atrophy is a common underlying feature of disease associated with C9orf72 mutations across its clinical phenotypes. Ventricular enlargement can be measured over a 6-month time frame, and appears to be faster in patients with cognitive impairment.

Background The Irish ALS Register is a population-based register of the epidemiological characteristics of amyotrophic lateral sclerosis (ALS) in the republic of Ireland. Objective To describe the clinical and demographic details of those patients included in the Irish ALS Register who were incorrectly diagnosed as having ALS (patients who were ultimately rediagnosed as having an "ALS mimic syndrome"). Methods The medical records of each patient referred to the register are routinely reviewed and, where possible, patients are examined by our group during their illness. Results Between January 1, 1993, and December 31, 1997, 32 patients (representing 7.3% of 437 referrals) were rediagnosed as having a condition other than ALS. The median age at onset for these 32 patients was 56.0 years (range, 19.5-85.8 years) for men and 53.5 years (range, 39.5-70.4 years) for women. Twenty-nine patients (91%) presented with symptoms referable to the limbs, and the remainder presented with symptoms involving the bulbar musculature. Multifocal motor neuropathy was the most common condition mistaken for ALS, accounting for 7 cases (22%), followed closely by Kennedy disease (4 cases [13%]). Factors leading to diagnostic revision included evolution of atypical symptoms, results of specific investigations, and failure of symptoms to progress. Twenty-seven (84%) of the patients with an ALS mimic syndrome fulfilled the El Escorial criteria for either "suspected" or "possible" ALS, 4 (13%) met the criteria for probable ALS, and 1 (3%) had definite ALS. Conclusions The application of the El Escorial diagnostic criteria may facilitate early recognition of non-ALS cases. Misdiagnosis of ALS remains a common clinical problem despite the increased availability of investigations and a greater awareness among neurologists of potential diagnostic pitfalls.

We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease. (C) 2012 Elsevier Inc. All rights reserved.