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1.  A Genetic Polymorphism of the Endogenous Opioid Dynorphin Modulates Monetary Reward Anticipation in the Corticostriatal Loop 
PLoS ONE  2014;9(2):e89954.
The dynorphin/κ-opioid receptor (KOP-R) system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype) of the variable nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC) when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses) of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.
PMCID: PMC3934978  PMID: 24587148
2.  Correction: RBFOX1 and RBFOX3 Mutations in Rolandic Epilepsy 
PLoS ONE  2013;8(10):10.1371/annotation/f6aed47b-9135-45f5-bfdd-f4ceb33c8561.
PMCID: PMC3823558  PMID: 24250743
3.  RBFOX1 and RBFOX3 Mutations in Rolandic Epilepsy 
PLoS ONE  2013;8(9):e73323.
Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy. The RBFOX1 protein and its homologues (RBFOX2 and RBFOX3) regulate alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. In this study, we explored if structural microdeletions and exonic sequence variations in RBFOX1, RBFOX2, RBFOX3 confer susceptibility to rolandic epilepsy (RE), a common idiopathic focal childhood epilepsy. By high-density SNP array screening of 289 unrelated RE patients, we identified two hemizygous deletions, a 365 kb deletion affecting two untranslated 5′-terminal exons of RBFOX1 and a 43 kb deletion spanning exon 3 of RBFOX3. Exome sequencing of 242 RE patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). Although the three variants were inherited from unaffected parents, they were present in all family members exhibiting the RE trait clinically or electroencephalographically with only one exception. In contrast, no deleterious mutations of RBFOX1 and RBFOX3 were found in the exomes of 6503 non-RE subjects deposited in the Exome Variant Server database. The observed RBFOX3 exon 3 deletion and nonsense mutation suggest that RBFOX3 represents a novel risk factor for RE, indicating that exon deletions and truncating mutations of RBFOX1 and RBFOX3 contribute to the genetic variance of partial and generalized idiopathic epilepsy syndromes.
PMCID: PMC3765197  PMID: 24039908
4.  Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A 
Kasperavičiūtė, Dalia | Catarino, Claudia B. | Matarin, Mar | Leu, Costin | Novy, Jan | Tostevin, Anna | Leal, Bárbara | Hessel, Ellen V. S. | Hallmann, Kerstin | Hildebrand, Michael S. | Dahl, Hans-Henrik M. | Ryten, Mina | Trabzuni, Daniah | Ramasamy, Adaikalavan | Alhusaini, Saud | Doherty, Colin P. | Dorn, Thomas | Hansen, Jörg | Krämer, Günter | Steinhoff, Bernhard J. | Zumsteg, Dominik | Duncan, Susan | Kälviäinen, Reetta K. | Eriksson, Kai J. | Kantanen, Anne-Mari | Pandolfo, Massimo | Gruber-Sedlmayr, Ursula | Schlachter, Kurt | Reinthaler, Eva M. | Stogmann, Elisabeth | Zimprich, Fritz | Théâtre, Emilie | Smith, Colin | O’Brien, Terence J. | Meng Tan, K. | Petrovski, Slave | Robbiano, Angela | Paravidino, Roberta | Zara, Federico | Striano, Pasquale | Sperling, Michael R. | Buono, Russell J. | Hakonarson, Hakon | Chaves, João | Costa, Paulo P. | Silva, Berta M. | da Silva, António M. | de Graan, Pierre N. E. | Koeleman, Bobby P. C. | Becker, Albert | Schoch, Susanne | von Lehe, Marec | Reif, Philipp S. | Rosenow, Felix | Becker, Felicitas | Weber, Yvonne | Lerche, Holger | Rössler, Karl | Buchfelder, Michael | Hamer, Hajo M. | Kobow, Katja | Coras, Roland | Blumcke, Ingmar | Scheffer, Ingrid E. | Berkovic, Samuel F. | Weale, Michael E. | Delanty, Norman | Depondt, Chantal | Cavalleri, Gianpiero L. | Kunz, Wolfram S. | Sisodiya, Sanjay M.
Brain  2013;136(10):3140-3150.
Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10−9, odds ratio (A) = 1.42, 95% confidence interval: 1.26–1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.
PMCID: PMC3784283  PMID: 24014518
mesial temporal lobe epilepsy; mesial temporal sclerosis; SCN1A; association; complex genetics
5.  Genetic characterization of northeastern Italian population isolates in the context of broader European genetic diversity 
Population genetic studies on European populations have highlighted Italy as one of genetically most diverse regions. This is possibly due to the country's complex demographic history and large variability in terrain throughout the territory. This is the reason why Italy is enriched for population isolates, Sardinia being the best-known example. As the population isolates have a great potential in disease-causing genetic variants identification, we aimed to genetically characterize a region from northeastern Italy, which is known for isolated communities. Total of 1310 samples, collected from six geographically isolated villages, were genotyped at >145 000 single-nucleotide polymorphism positions. Newly genotyped data were analyzed jointly with the available genome-wide data sets of individuals of European descent, including several population isolates. Despite the linguistic differences and geographical isolation the village populations still show the greatest genetic similarity to other Italian samples. The genetic isolation and small effective population size of the village populations is manifested by higher levels of genomic homozygosity and elevated linkage disequilibrium. These estimates become even more striking when the detected substructure is taken into account. The observed level of genetic isolation in Friuli-Venezia Giulia region is more extreme according to several measures of isolation compared with Sardinians, French Basques and northern Finns, thus proving the status of an isolate.
PMCID: PMC3658181  PMID: 23249956
population genetics; isolated population; genetic distance
6.  Dynamic Up-regulation of Prodynorphin Transcription in Temporal Lobe Epilepsy 
Hippocampus  2009;19(11):1051-1054.
Dynorphin neuropeptides are believed to act as endogenous anticonvulsants, though direct evidence for such a role in humans is sparse. We now report pronounced increases of prodynorphin mRNA expression in the dentate gyrus of patients with temporal lobe epilepsy in comparison to controls. We detected a conspicuously right skewed, bimodal distribution of mRNA levels among patients, suggestive of a dynamic up-regulation of prodynorphin expression in epilepsy. Highest transcript levels were seen postictally. Our data argue for an essential role of dynorphin in the termination of seizures.
PMCID: PMC3073604  PMID: 19437412
dynorphin; neuropeptides; temporal lobe epilepsy; seizures; seizure protection
7.  15q13.3 microdeletions increase risk of idiopathic generalized epilepsy 
Nature genetics  2009;41(2):160-162.
We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 × 10−8). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
PMCID: PMC3026630  PMID: 19136953
8.  Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies 
Brain  2009;133(1):23-32.
Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8–13.2; χ2 = 26.7; 1 degree of freedom; P = 2.4 × 10−7). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8–13.2; P = 4.2 × 10−4) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3–74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
PMCID: PMC2801323  PMID: 19843651
idiopathic generalized epilepsy; microdeletions; association; genetics
9.  Role of LINGO1 polymorphisms in Parkinson’s disease 
A clinical overlap between Parkinson’s disease (PD) and essential tremor (ET) has prompted a discussion whether these conditions share common genetic susceptibility factors. Recently, the first genome-wide association study in ET revealed a significant association with a variant in the LINGO1 gene. LINGO1 has also been demonstrated to play a role in the survival of dopaminergic neurons in an animal model of PD, and therefore constitutes a potential candidate gene for PD. In this present study, SNPs rs9652490, rs11856808, rs7177008 of LINGO1 were genotyped in a total of 694 Austrian subjects (349 PD, 345 controls). No association could be found between genotype or allele counts and PD. Neither did a subgroup analysis in tremor-dominant PD patients reveal a significant association. This study on LINGO1-variants in PD argues against a major role of LINGO1 gene variations for PD.
PMCID: PMC2798904  PMID: 19908305
Essential Tremor; Parkinson’s disease; LINGO1; genetics; association study
10.  Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures 
PLoS ONE  2010;5(9):e12740.
Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE.
Methodology/Principal Findings
A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS.
The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.
PMCID: PMC2940893  PMID: 20862287
12.  Genetic Structure of Europeans: A View from the North–East 
PLoS ONE  2009;4(5):e5472.
Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (λ) (ranging from 1.00 to 4.21), fixation index (Fst) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS).
PMCID: PMC2675054  PMID: 19424496
13.  Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans 
PLoS Biology  2005;3(12):e387.
Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee–human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.
Strong positive selection has resulted in changes to the regulation of the human prodynorphin gene, with evidence for increased expression as compared with chimp. Additionally, recent selection has led to different alleles in different parts of the world.
PMCID: PMC1283535  PMID: 16274263

Results 1-13 (13)