Identification of Six Novel SOD1 Gene Mutations in Familial Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SODl) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SODl mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protei

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Genetics of restless legs syndrome.

At the outset of genetic studies in restless legs syndrome (RLS), the disorder was assumed to be a classical monogenic disorder that runs in families. However, years of family studies did not reveal any causally-related genes or genetic variants. The advent of high-throughput genotyping technology led to a change; genome-wide association studies in large case-control samples became feasible, which led to the identification of first genetic risk variants for RLS. Variants detected by this approach are common ones, which that individually confer only a minor increase in risk of disease. Overall, the currently known risk variants in six genomic loci account for only a small proportion of the genetically determined susceptibility to RLS. Additional risk loci and individual variants remain to be discovered. First studies indicate that rare genetic variants are also important contributors in RLS. These are expected to have a larger impact on the phenotype and may thus prove to be excellent candidates for functional studies and, in the long-term, targets for developing therapeutics or preventive measures. To enable their discovery, large-scale studies including tens of thousands of affected individuals may be needed. Next-generation sequencing technologies such as whole exome or whole genome sequencing will be essential for this endeavor. Even though the number of known risk variants is still limited, they have been indispensable in terms of deciphering the underlying pathophysiology of RLS, providing the molecular starting points for animal models and in vitro studies to understand disease mechanisms. In addition, genetic risk variants can be valuable tools for disentangling the phenotypic complexity observed in RLS. Testing RLS risk variants for associations with periodic limb movements (PLMs) identified a significant role of some of the variants and suggested PLMs as an endophenotype in RLS. Further advances in genetics research in RLS will be driven by large-scale sequencing projects and the identification of additional common, but also rarer risk variants with larger effects on disease risk. Another uncharted territory in RLS research epigenetic effect on gene activity. Overall, genetic studies continue to hold great potential for understanding biology of the disease

A New Locus For Generalized Epilepsy With Febrile Seizures Plus Maps To Chromosome 2

Generalized epilepsy with febrile seizures plus (GEFS+) is a recently recognized but relatively common form of inherited childhood-onset epilepsy with heterogeneous epilepsy phenotypes. We genotyped 41 family members, including 21 affected individuals, to localize the gene causing epilepsy in a large family segregating an autosomal dominant form of GEFS+. A genomewide search examining 197 markers identified linkage of GEFS+ to chromosome 2, on the basis of an initial positive LOD score for marker D2S294 (Z = 4.4, recombination fraction [θ] = 0). A total of 24 markers were tested on chromosome 2q, to define the smallest candidate region for GEFS+. The highest two-point LOD score (Z(max) = 5.29; θ = 0) was obtained with marker D2S324. Critical recombination events mapped the GEFS+ gene to a 29-cM region flanked by markers D2S156 and D2S311, with the idiopathic generalized epilepsy locus thereby assigned to chromosome 2q23-q31. The existence of the heterogeneous epilepsy phenotypes in this kindred suggests that seizure predisposition determined by the GEFS+ gene on chromosome 2q could be modified by other genes and/or by environmental factors, to produce the different seizure types observed.662698701Blair, L.A., Levitan, E.S., Marshall, J., Dionne, V.E., Barnard, E.A., Single sub-units of the GABAA receptor form ion channels with properties of the native receptor (1988) Science, 242, pp. 577-579Baulac, S., Gourfinkel-An, I., Picard, F., Rosenberg-Bourgin, M., Prud'homme, J.-F., Baulac, M., Brice, A., A second locus for familial generalized epilepsy with febrile seizures plus maps to chromosome 2q21-q33 (1999) Am J Hum Genet, 65, pp. 1078-1085Berkovic, S.F., Scheffer, I.E., Genetics of the epilepsies (1999) Curr Opin Neurol, 12, pp. 177-182Bievert, C., Schoeder, B.C., Kubisch, C., Berkovic, S.F., Propping, P., Jentsch, T.J., Steinlein, O.K., A potassium channel mutation in neonatal human epilepsy (1998) Science, 279, pp. 403-406Bu, D.F., Tobin, A.J., The exon-intron organization of the genes (GAD1 and GAD2) encoding two human glutamate decarboxylases (GAD67 and GAD65) suggests that they derive from a common ancestral GAD (1994) Genomics, 21, pp. 222-228Proposal for revised clinical and electroencephalographic classification of epileptic seizures (1981) Epilepsia, 22, pp. 489-501Gyapay, G., Morissette, J., Vignal, A., Dib, C., Fizames, C., Millasseau, P., Marc, S., The 1993-94 Généthon human genetic linkage map (1994) Nat Genet, 7, pp. 246-339Hauser, W.A., Annegers, J.F., Kurland, L.T., Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984 (1993) Epilepsia, 34, pp. 453-468Lathrop, G.M., Lalouel, J.M., Easy calculations of LOD scores and genetic risks on small computers (1984) Am J Hum Genet, 36, pp. 460-465Lopes-Cendes, I., Scheffer, I.E., Berkovic, S.F., Rousseau, M., Andermann, E., Rouleau, G.A., Mapping a locus for idiopathic generalized epilepsy in a large multiplex family (1996) Epilepsia, 37 (SUPPL. 5), p. 127Moulard, B., Guipponi, M., Chaigne, D., Mouthon, D., Buresi, C., Malafosse, A., Identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+) on chromosome 2q24-q33 (1999) Am J Hum Genet, 65, pp. 1396-1400Peiffer, A., Thompson, J., Charlier, C., Otterud, B., Varvil, T., Pappas, C., Barnitz, C., A locus for febrile seizures (FEB3) maps to chromosome 2q23-24 (1999) Ann Neurol, 46, pp. 671-678Sambrook, J., Fritsch, E.F., Maniatis, T., (1989) Molecular Cloning: A Laboratory Manual, 2d Ed., pp. E3-E4. , Cold Spring Harbor Laboratory, Cold Spring Harbor, NYScheffer, I.E., Berkovic, S.F., Generalized epilepsy with febrile seizures plus: A genetic disorder with heterogeneous clinical phenotypes (1997) Brain, 120, pp. 479-490Singh, N.A., Charlier, C., Stauffer, D., DuPont, B.R., Leach, R.J., Melis, R., Ronen, G.M., A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns (1998) Nat Genet, 18, pp. 25-29Singh, R., Scheffer, I.E., Crossland, K., Berkovic, S.F., Generalized epilepsy with febrile seizures plus (GEFS+): A common, childhood-onset, genetic epilepsy syndrome (1999) Ann Neurol, 45, pp. 75-81Steinlein, O.K., Mulley, J.C., Propping, P., Wallace, R.H., Phillips, H.A., Sutherland, G.R., Scheffer, I.E., A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy (1995) Nat Genet, 11, pp. 201-203Wallace, R.H., Wang, D.W., Sing, R., Scheffer, I.E., George A.I., Jr., Phillips, H.A., Saar, K., Febrile seizures and generalized epilepsy associated with a mutation in the Na +-channel β1 subunit gene SCN1B (1998) Nat Genet, 19, pp. 366-37