The evolutionary origin of psychosis.

Imagination, the driving force of creativity, and primary psychosis are human-specific, since we do not observe behaviors in other species that would convincingly suggest they possess the same traits. Both these traits have been linked to the function of the prefrontal cortex, which is the most evolutionarily novel region of the human brain. A number of evolutionarily novel genetic and epigenetic changes that determine the human brain-specific structure and function have been discovered in recent years. Among them are genomic loci subjected to increased rates of single nucleotide substitutions in humans, called human accelerated regions. These mostly regulatory regions are involved in brain development and sometimes contain genetic variants that confer a risk for schizophrenia. On the other hand, neuroimaging data suggest that mind wandering and related phenomena (as a proxy of imagination) are in many ways similar to rapid eye movement dreaming, a function also present in non-human species. Furthermore, both functions are similar to psychosis in several ways: for example, the same brain areas are activated both in dreams and visual hallucinations. In the present Perspective we hypothesize that imagination is an evolutionary adaptation of dreaming, while primary psychosis results from deficient control by higher-order brain areas over imagination. In the light of this, human accelerated regions might be one of the key drivers in evolution of human imagination and the pathogenesis of psychotic disorders.

Genomic regulatory sequences in the pathogenesis of bipolar disorder.

The lifetime prevalence of bipolar disorder is estimated to be about 2%. Epigenetics defines regulatory mechanisms that determine relatively stable patterns of gene expression by controlling all key steps, from DNA to messenger RNA to protein. This Mini Review highlights recent discoveries of modified epigenetic control resulting from genetic variants associated with bipolar disorder in genome-wide association studies. The revealed epigenetic abnormalities implicate gene transcription and post-transcriptional regulation. In the light of these discoveries, the Mini Review focuses on the genes PACS1, MCHR1, DCLK3, HAPLN4, LMAN2L, TMEM258, GNL3, LRRC57, CACNA1C, CACNA1D, and NOVA2 and their potential biological role in the pathogenesis of bipolar disorder. Molecular mechanisms under control of these genes do not translate into a unified picture and substantially more research is needed to fill the gaps in knowledge and to solve current limitations in prognosis and treatment of bipolar disorder. In conclusion, the genetic and functional studies confirm the complex nature of bipolar disorder and indicate future research directions to explore possible targeted treatment options, eventually working toward a personalized approach.

A Genome-Wide Association Study Reveals a BDNF-Centered Molecular Network Associated with Alcohol Dependence and Related Clinical Measures.

At least 50% of factors predisposing to alcohol dependence (AD) are genetic and women affected with this disorder present with more psychiatric comorbidities, probably indicating different genetic factors involved. We aimed to run a genome-wide association study (GWAS) followed by a bioinformatic functional annotation of associated genomic regions in patients with AD and eight related clinical measures. A genome-wide significant association of rs220677 with AD (p-value = 1.33 × 10-8 calculated with the Yates-corrected χ2 test under the assumption of dominant inheritance) was discovered in female patients. Associations of AD and related clinical measures with seven other single nucleotide polymorphisms listed in previous GWASs of psychiatric and addiction traits were differently replicated in male and female patients. The bioinformatic analysis showed that regulatory elements in the eight associated linkage disequilibrium blocks define the expression of 80 protein-coding genes. Nearly 68% of these and of 120 previously published coding genes associated with alcohol phenotypes directly interact in a single network, where BDNF is the most significant hub gene. This study indicates that several genes behind the pathogenesis of AD are different in male and female patients, but implicated molecular mechanisms are functionally connected. The study also reveals a central role of BDNF in the pathogenesis of AD.

Rare single nucleotide variants in COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482.

BACKGROUND: Keratoconus is a chronic degenerative disorder of the cornea characterized by thinning and cone-shaped protrusions. Although genetic factors play a key role in keratoconus development, the etiology is still under investigation. The occurrence of single-nucleotide polymorphisms (SNPs) associated with keratoconus in Russian patients is poorly studied. The purpose of this study was to validate whether three reported keratoconus-associated SNPs (rs1536482 near the COL5A1 gene, rs2721051 near the FOXO1 gene, rs1324183 near the MPDZ gene) are also actual for a Russian cohort of patients. Additionally, we investigated the COL5A1 promoter sequence for single-nucleotide variants (SNVs) in a subgroup of keratoconus patients with at least one rs1536482 minor allele (rs1536482+) to assess the role of these SNVs in keratoconus susceptibility associated with rs1536482. METHODS: This case-control study included 150 keratoconus patients and two control groups (main and additional, 205 and 474 participants, respectively). We performed PCR targeting regions flanking SNVs and the COL5A1 promoter, followed by Sanger sequencing of amplicons. The additional control group was genotyped using an SNP array. RESULTS: The minor allele frequency was significantly different between the keratoconus and control cohorts (main and combined) for rs1536482, rs2721051, and rs1324183 (p-value < 0.05). The rare variants rs1043208782 and rs569248712 were found in the COL5A1 promoter in two out of 94 rs1536482+ keratoconus patients. CONCLUSION: rs1536482, rs2721051, and rs1324183 were associated with keratoconus in a Russian cohort. SNVs in the COL5A1 promoter do not play a major role in keratoconus susceptibility associated with rs1536482.

A genome-wide association study identifies a gene network associated with paranoid schizophrenia and antipsychotics-induced tardive dyskinesia.

In the present study we conducted a genome-wide association study (GWAS) in a cohort of 505 patients with paranoid schizophrenia (SCZ), of which 95 had tardive dyskinesia (TD), and 503 healthy controls. Using data generated by the PsychENCODE Consortium (PEC) and other bioinformatic databases, we revealed a gene network, implicated in neurodevelopment and brain function, associated with both these disorders. Almost all these genes are in gene or isoform co-expression PEC network modules important for the functioning of the brain; the activity of these networks is also altered in SCZ, bipolar disorder and autism spectrum disorders. The associated PEC network modules are enriched for gene ontology terms relevant to the brain development and function (CNS development, neuron development, axon ensheathment, synapse, synaptic vesicle cycle, and signaling receptor activity) and to the immune system (inflammatory response). Results of the present study suggest that orofacial and limbtruncal types of TD seem to share the molecular network with SCZ. Paranoid SCZ and abnormal involuntary movements that indicate the orofacial type of TD are associated with the same genomic loci on chromosomes 3p22.2, 8q21.13, and 13q14.2. The limbtruncal type of TD is associated with a locus on chromosome 3p13 where the best functional candidate is FOXP1, a high-confidence SCZ gene. The results of this study shed light on common pathogenic mechanisms for SCZ and TD, and indicate that the pathogenesis of the orofacial and limbtruncal types of TD might be driven by interacting genes implicated in neurodevelopment.

NRG1, PIP4K2A, and HTR2C as Potential Candidate Biomarker Genes for Several Clinical Subphenotypes of Depression and Bipolar Disorder.

GSK3B, BDNF, NGF, NRG1, HTR2C, and PIP4K2A play important roles in molecular mechanisms of psychiatric disorders. GSK3B occupies a central position in these molecular mechanisms and is also modulated by psychotropic drugs. BDNF regulates a number of key aspects in neurodevelopment and synaptic plasticity. NGF exerts a trophic action and is implicated in cerebral alterations associated with psychiatric disorders. NRG1 is active in neural development, synaptic plasticity, and neurotransmission. HTR2C is another important psychopharmacological target. PIP4K2A catalyzes the phosphorylation of PI5P to form PIP2, the latter being implicated in various aspects of neuronal signal transduction. In the present study, the six genes were sequenced in a cohort of 19 patients with bipolar affective disorder, 41 patients with recurrent depressive disorder, and 55 patients with depressive episode. The study revealed a number of genetic variants associated with antidepressant treatment response, time to recurrence of episodes, and depression severity. Namely, alleles of rs35641374 and rs10508649 (NRG1 and PIP4K2A) may be prognostic biomarkers of time to recurrence of depressive and manic/mixed episodes among patients with bipolar affective disorder. Alleles of NC_000008.11:g.32614509_32614510del, rs61731109, and rs10508649 (also NRG1 and PIP4K2A) seem to be predictive biomarkers of response to pharmacological antidepressant treatment on the 28th day assessed by the HDRS-17 or CGI-I scale. In particular, the allele G of rs10508649 (PIP4K2A) may increase resistance to antidepressant treatment and be at the same time protective against recurrent manic/mixed episodes. These results support previous data indicating a biological link between resistance to antidepressant treatment and mania. Bioinformatic functional annotation of associated variants revealed possible impact for transcriptional regulation of PIP4K2A. In addition, the allele A of rs2248440 (HTR2C) may be a prognostic biomarker of depression severity. This allele decreases expression of the neighboring immune system gene IL13RA2 in the putamen according to the GTEx portal. The variant rs2248440 is near rs6318 (previously associated with depression and effects of psychotropic drugs) that is an eQTL for the same gene and tissue. Finally, the study points to several protein interactions relevant in the pathogenesis of mood disorders. Functional studies using cellular or animal models are warranted to support these results.

Current challenges and possible future developments in personalized psychiatry with an emphasis on psychotic disorders.

A personalized medicine approach seems to be particularly applicable to psychiatry. Indeed, considering mental illness as deregulation, unique to each patient, of molecular pathways, governing the development and functioning of the brain, seems to be the most justified way to understand and treat disorders of this medical category. In order to extract correct information about the implicated molecular pathways, data can be drawn from sampling phenotypic and genetic biomarkers and then analyzed by a machine learning algorithm. This review describes current difficulties in the field of personalized psychiatry and gives several examples of possibly actionable biomarkers of psychotic and other psychiatric disorders, including several examples of genetic studies relevant to personalized psychiatry. Most of these biomarkers are not yet ready to be introduced in clinical practice. In a next step, a perspective on the path personalized psychiatry may take in the future is given, paying particular attention to machine learning algorithms that can be used with the goal of handling multidimensional datasets.

No evidence so far of a major role of AKT1 and GSK3B in the pathogenesis of antipsychotic-induced tardive dyskinesia.

OBJECTIVE: AKT1 and GSK3B take part in one of the intracellular cascades activated by the D2 dopamine receptor (DRD2). This receptor is antagonized by antipsychotics and plays a role in the pathogenesis of antipsychotic-induced tardive dyskinesia (TD). The present study investigated association of several polymorphisms in the two candidate genes, AKT1 and GSK3B, with TD in antipsychotic-treated patients with schizophrenia. METHODS: DNA samples from 449 patients from several Siberian regions (Russia) were genotyped, and the results were analyzed using chi-squared tests and analyses of variance. RESULTS: Antipsychotic-induced TD was not associated with either of the tested functional polymorphisms (rs334558, rs1130214, and rs3730358). CONCLUSIONS: Despite regulation of AKT1 and GSK3B by DRD2, we found no evidence that these two kinases play a major role in the pathogenesis of antipsychotic-induced TD. These results agree with previously published data and necessitate further exploration of other pathogenic mechanisms, such as neurotoxicity due to excessive dopamine metabolism.

The functional variant rs334558 of GSK3B is associated with remission in patients with depressive disorders.

PURPOSE: GSK3B and AKT1 genes have been implicated in the pathogenesis of a number of psychiatric and neurological disorders. Furthermore, their genetic variants are associated with response to antidepressant pharmacotherapy. As the evidence is still incomplete and inconsistent, continuing efforts to investigate the role of these two genes in the pathogenesis and treatment of brain disorders is necessary. The aim of our study was thus to evaluate the association of variants of these two genes with depressive disorders and drug treatment response. PATIENTS AND METHODS: In the present study, 222 patients with a depressive disorder who underwent pharmacological antidepressant treatment were divided into remitters and non-remitters following a 28-day course of pharmacotherapy. The association of a depressive disorder and remission rates with polymorphisms rs334558 in the GSK3B gene and rs1130214 and rs3730358 in the AKT1 gene was evaluated with a chi-square test. RESULTS: Neither of the studied genetic variants was associated with a depressive disorder. Furthermore, frequencies of alleles and genotypes for rs1130214 and rs3730358 were not different in the groups of remitters and non-remitters. However, the activating allele T of the functional polymorphism rs334558 was significantly associated with remission, when all types of antidepressant drugs were included. This association continued as a trend when only patients taking selective serotonin reuptake inhibitors were considered. CONCLUSION: The present study provides support that the functional polymorphism rs334558 of GSK3B may play a role as a useful genetic and pharmacogenetic biomarker in the framework of personalized medicine approach.

Human Accelerated Regions and Other Human-Specific Sequence Variations in the Context of Evolution and Their Relevance for Brain Development.

The review discusses, in a format of a timeline, the studies of different types of genetic variants, present in Homo sapiens, but absent in all other primate, mammalian, or vertebrate species, tested so far. The main characteristic of these variants is that they are found in regions of high evolutionary conservation. These sequence variations include single nucleotide substitutions (called human accelerated regions), deletions, and segmental duplications. The rationale for finding such variations in the human genome is that they could be responsible for traits, specific to our species, of which the human brain is the most remarkable. As became obvious, the vast majority of human-specific single nucleotide substitutions are found in noncoding, likely regulatory regions. A number of genes, associated with these human-specific alleles, often through novel enhancer activity, were in fact shown to be implicated in human-specific development of certain brain areas, including the prefrontal cortex. Human-specific deletions may remove regulatory sequences, such as enhancers. Segmental duplications, because of their large size, create new coding sequences, like new functional paralogs. Further functional study of these variants will shed light on evolution of our species, as well as on the etiology of neurodevelopmental disorders.

Beta-catenin in schizophrenia: Possibly deleterious novel mutation.

Schizophrenia is a debilitating psychiatric disorder, affecting approximately 1% of the human population. Mostly genetic factors contribute to schizophrenia, but the genetics are complex and various aspects of brain functioning and structure, from development to synapse plasticity, seem to be involved in the pathogenesis. The goal of the study was to look for novel mutations in genes, implicated in molecular networks, important in schizophrenia. In the study four candidate genes taking part in the WNT signaling pathway were analyzed by sequencing in a cohort of 87 schizophrenia patients from Saint Petersburg, Russia. The gene list included CTNNB1 (beta-catenin), GSK3B, WNT2B and WNT7B. The impact of discovered variants on the protein function was analyzed in silico. We found three variants in the genes CTNNB1 and WNT7B, absent in healthy controls, including 212 controls from the same geographic area. The novel mutation c.1943A>G (p.N648S) in CTNNB1 seems to be the best candidate for disease-associated mutation in this study, as it damages the protein product in silico. This is the first study reporting mutations in CTNNB1 in schizophrenia.

Sequencing of five left-right cerebral asymmetry genes in a cohort of schizophrenia and schizotypal disorder patients from Russia.

OBJECTIVE: Schizophrenia is a severe psychiatric disorder, affecting ∼1% of the human population. The genetic contribution to schizophrenia is significant, but the genetics are complex and many aspects of brain functioning, from neural development to synapse structure, seem to be involved in the pathogenesis. A novel way to study the molecular causes of schizophrenia is to study the genetics of left-right (LR) brain asymmetry, the disease feature often observed in schizophrenic patients. METHODS: In this study, we analyzed by sequencing five candidate LR cerebral asymmetry genes in a cohort of 95 schizophrenia and schizotypal disorder patients from Saint Petersburg, Russia. The gene list included LMO4, LRRTM1, FOXP2, the PCDH11X/Y gene pair, and SRY. RESULTS: We found 17 previously unreported variants in the genes LRRTM1, FOXP2, LMO4, and PCDH11X in the 3'-UTR and 5'-UTR. The variants might contribute toward an altered mRNA processing, which could lead to altered mRNA amounts in developing neurons of the brain and establishment of an incorrect LR asymmetry profile. CONCLUSION: This is the first study in which multiple candidate genes for cerebral LR asymmetry and schizophrenia have been analyzed by sequencing. The approach to study the genetics of schizophrenia from the perspective of an LR cerebral asymmetry disturbance deserves more attention.

Family study of restless legs syndrome in Quebec, Canada: clinical characterization of 671 familial cases.

OBJECTIVES: To fully ascertain the familial aggregation of restless legs syndrome (RLS) and to characterize the clinical features of familial RLS (fRLS) cases. DESIGN: A case series survey with a high response rate. SETTING: Academic research center. PARTICIPANTS: Consecutive RLS probands (n = 249) were followed up in a specialized sleep center for 15 years. A total of 671 cases of fRLS met the current standard diagnostic criteria, including 192 probands characterized using multidimensional clinical assessments and 479 affected family members assessed by their responses to a structured questionnaire telephone diagnostic interview. MAIN OUTCOME MEASURES: Sibling and offspring relative risk ratio and clinical and genetic features of patients with fRLS and families. RESULTS: Our data showed that RLS aggregates in families with a familial rate of 77%, a sibling relative risk of 3.6 (95% confidence interval, 2.8-4.4), and an offspring relative risk of 1.8 (1.0-2.7). Familial RLS is a chronic disorder with a mean (SD) disease duration of 24 (16) years and a wide range of age of onset (mean [SD], 28 [15] years), with most family members having early-onset disease but mild to moderate RLS symptoms. Our clinical data also indicated that fRLS is more prominent among women who also had increased incidence of anemia/iron deficiency, arthritis, and number of pregnancies. Pregnancy-related RLS seems to be a characteristic feature of fRLS, and afflicted women tend to have a much younger age of onset. CONCLUSIONS: Restless legs syndrome significantly aggregated in families with variable phenotypic expressivity, and the siblings of severely affected individuals have an increased risk of developing the disease.

Association of intronic variants of the BTBD9 gene with Tourette syndrome.

OBJECTIVE: To test the association between Tourette syndrome (TS) and genetic variants in genomic loci MEIS1, MAP2K5/LBXCOR1, and BTBD9, for which genome-wide association studies in restless legs syndrome and periodic limb movements during sleep revealed common risk variants. DESIGN: Case-control association study. SETTING: Movement disorder clinic in Montreal. Subjects We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects. MAIN OUTCOME MEASURES: Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder. RESULTS: The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (chi(2) = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (chi(2) = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score. CONCLUSION: Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mRNA and protein expression levels.

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs at night, which is often accompanied by unpleasant sensations. A recent genomewide association study identified an association between RLS and intronic markers from the MEIS1 gene. Comparative genomic analysis indicates that MEIS1 is the only gene encompassed in this evolutionarily conserved chromosomal segment, i.e. a conservation synteny block, from mammals to fish. We carried out a series of experiments to delineate the role of MEIS1 in RLS pathogenesis and the underlying genetic mechanism. We sequenced all 13 MEIS1 exons and their splice junctions in 285 RLS probands with confirmed clinical diagnosis and did not identify any causative coding or exon-intron junction mutations. We found no evidence of structural variation or disease-associated haplotype differential splicing. However, sequencing of conserved regions of MEIS1 introns 8 and 9 identified a novel single nucleotide polymorphism (C13B_2) significantly associated with RLS (allelic association, P = 1.81E-07). We detected a significant decrease in MEIS1 mRNA expression by quantitative real-time polymerase chain reaction in lymphoblastoid cell lines (LCLs) and brain tissues from RLS patients homozygous for the intronic RLS risk haplotype, compared with those homozygous for the non-risk haplotype. Finally, we found significantly decreased MEIS1 protein levels in the same batch of LCLs and brain tissues from the homozygous carriers of the risk haplotype, compared with the homozygous non-carriers. Therefore, these data suggest that reduced expression of the MEIS1 gene, possibly through intronic cis-regulatory element(s), predisposes to RLS.

Autosomal-dominant locus for Restless Legs Syndrome in French-Canadians on chromosome 16p12.1.

We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.

Genetic association studies of neurotensin gene and restless legs syndrome in French Canadians.

BACKGROUND AND PURPOSE: The neurotensin gene (NTS), a known dopamine modulator, is located within the candidate region for the first genetic locus of restless legs syndrome (RLS1) on chromosome 12q. Though no causative mutation was found in selected patients in a previous mutation analysis, the involvement of NTS in RLS cannot be completely excluded as a potential positional and functional candidate gene. The purpose of the current study is to further explore the NTS gene for potential functional variant(s) in its entire genomic and potential regulatory regions and their possible association with RLS symptoms. METHODS AND SUBJECTS: We resequenced the coding regions and sequenced all the intronic and potential regulatory regions of the NTS gene in additional patients and controls. We carried out full scale gene-based case-control and family-based genetic association studies using the sequence variants detected during mutational analysis. RESULTS: No coding or variants in regulatory and intronic regions compatible with a deleterious mutation were detected. Seven polymorphisms with elevated allele frequencies in the Caucasian population did not show association with RLS in two independent case-control groups and 110 RLS families. CONCLUSION: The NTS gene on chromosome 12q is most unlikely to play a direct role in RLS etiology.

Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families.

Converging evidence from clinical observations, brain imaging and pathological findings strongly indicate impaired brain iron regulation in restless legs syndrome (RLS). Animal models with mutation in (DMT1) divalent metal transporter 1 gene, an important brain iron transporter, demonstrate a similar iron deficiency profile as found in RLS brain. The human DMT1 gene, mapped to chromosome 12q near the RLS1 locus, qualifies as an excellent functional and possible positional candidate for RLS. DMT1 protein levels were assessed in lymphoblastoid cell lines from RLS patients and controls. Linkage analyses were carried out with markers flanking and within the DMT1 gene. Selected patient samples from RLS families with compatible linkage to the RLS1 locus on 12q were fully sequenced in both the coding regions and the long stretches of UTR sequences. Finally, selected sequence variants were further studied in case/control and family-based association tests. A clinical association of anemia and RLS was further confirmed in this study. There was no detectable difference in DMT1 protein levels between RLS patient lymphoblastoid cell lines and normal controls. Non-parametric linkage analyses failed to identify any significant linkage signals within the DMT1 gene region. Sequencing of selected patients did not detect any sequence variant(s) compatible with DMT1 harboring RLS causative mutation(s). Further studies did not find any association between ten SNPs, spanning the whole DMT1 gene region, and RLS affection status. Finally, two DMT1 intronic SNPs showed positive association with RLS in patients with a history of anemia, when compared to RLS patients without anemia.

TAU mutations are not a predominant cause of frontotemporal dementia in Canadian patients.

OBJECTIVE: Frontotemporal dementia is a neurodegenerative disease affecting mostly the frontal and/or temporal lobes, with neuronal loss and intraneuronal and/or intraglial inclusions composed of hyperphosphorylated microtubule-associated protein tau and ubiquitin. Missense and splice site mutations in the TAU gene have been identified in approximately 15% of all frontotemporal dementia cases. In this study, we evaluated the involvement of mutations in the TAU gene in development of frontotemporal dementia phenotype in patients of French or English Canadian origins. METHODS: Fourteen patients with frontotemporal dementia phenotype and 98 normal controls were recruited for the study. The TAU gene was screened by sequencing and denaturing high performance liquid chromatography. RESULTS: No mutations, except some new polymorphisms, were detected in the TAU gene of these patients. One polymorphism, however, may play a role in pathogenesis. CONCLUSION: Our results agree with previous work suggesting that mutations in this gene are not a frequent cause of the frontotemporal dementia phenotype in Canadian patients.

The 14q restless legs syndrome locus in the French Canadian population.

A new restless legs syndrome locus on chromosome 14 recently has been reported in one family of Italian origin. Our study aimed to replicate this finding and determine the importance of this locus in the French Canadian population. Markers spanning the region were genotyped in 14 large families and linkage assessed using two-point and multipoint logarithm of odds scores. Possible linkage to this locus was found in one of our kindreds providing support for the existence of this locus and indicating that this locus may be responsible for a small fraction of French Canadian restless legs syndrome.