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1.
Mol Psychiatry ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492941

RESUMO

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

2.
Nat Neurosci ; 22(7): 1066-1074, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209380

RESUMO

Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 cases and 48,985 controls, followed by replication in 5,501 cases and 301,041 controls. We report a genome-wide significant risk locus for CUD (P = 9.31 × 10-12) that replicates in an independent population (Preplication = 3.27 × 10-3, Pmeta-analysis = 9.09 × 10-12). The index variant (rs56372821) is a strong expression quantitative trait locus for cholinergic receptor nicotinic α2 subunit (CHRNA2); analyses of the genetically regulated gene expression identified a significant association of CHRNA2 expression with CUD in brain tissue. At the polygenic level, analyses revealed a significant decrease in the risk of CUD with increased load of variants associated with cognitive performance. The results provide biological insights and inform on the genetic architecture of CUD.


Assuntos
Abuso de Maconha/genética , Proteínas do Tecido Nervoso/fisiologia , Receptores Nicotínicos/fisiologia , Idade de Início , Alelos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Encéfalo/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 8/genética , Cognição/fisiologia , Estudos de Coortes , Fatores de Confusão (Epidemiologia) , Dinamarca , Escolaridade , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Herança Multifatorial , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Receptores Nicotínicos/biossíntese , Receptores Nicotínicos/genética , Esquizofrenia/genética , Fumar/genética , Transcriptoma
4.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified 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. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
6.
Nat Genet ; 51(4): 659-674, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911161

RESUMO

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.


Assuntos
Encéfalo/fisiopatologia , Expressão Gênica/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Risco , Transcriptoma/genética
7.
Nat Genet ; 51(3): 431-444, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804558

RESUMO

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Dinamarca , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Herança Multifatorial/genética , Fenótipo , Fatores de Risco
8.
PLoS One ; 13(12): e0208829, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30543675

RESUMO

Mitochondrial DNA (mtDNA) haplogroups (hgs) are evolutionarily conserved sets of mtDNA SNP-haplotypes with characteristic geographical distribution. Associations of hgs with disease and physiological characteristics have been reported, but have frequently not been reproducible. Using 418 mtDNA SNPs on the PsychChip (Illumina), we assessed the spatio-temporal distribution of mtDNA hgs in Denmark from DNA isolated from 24,642 geographically un-biased dried blood spots (DBS), collected from 1981 to 2005 through the Danish National Neonatal Screening program. ADMIXTURE was used to establish the genomic ancestry of all samples using a reference of 100K+ autosomal SNPs in 2,248 individuals from nine populations. Median-joining analysis determined that the hgs were highly variable, despite being typically Northern European in origin, suggesting multiple founder events. Furthermore, considerable heterogeneity and variation in nuclear genomic ancestry was observed. Thus, individuals with hg H exhibited 95%, and U hgs 38.2% - 92.5%, Danish ancestry. Significant clines between geographical regions and rural and metropolitan populations were found. Over 25 years, macro-hg L increased from 0.2% to 1.2% (p = 1.1*E-10), and M from 1% to 2.4% (p = 3.7*E-8). Hg U increased among the R macro-hg from 14.1% to 16.5% (p = 1.9*E-3). Genomic ancestry, geographical skewedness, and sub-hg distribution suggested that the L, M and U increases are due to immigration. The complex spatio-temporal dynamics and genomic ancestry of mtDNA in the Danish population reflect repeated migratory events and, in later years, net immigration. Such complexity may explain the often contradictory and population-specific reports of mito-genomic association with disease.


Assuntos
DNA Mitocondrial , Grupo com Ancestrais do Continente Europeu/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Dinamarca , Genética Populacional , Humanos
9.
PLoS One ; 13(12): e0208828, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30532134

RESUMO

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. An analysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 Danes without a psychiatric diagnosis and 2,538 schizophrenia patients, revealed marked inter-allelic differences in mitochondrial haplogroup affiliation and nuclear ancestry. This bi-genomic dependence could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation and nuclear ancestry. The extensive bi-genomic dependence documented here is a major concern when interpreting historic, as well as designing future, mtDNA association studies.


Assuntos
DNA Mitocondrial/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino
10.
Nat Genet ; 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30478444

RESUMO

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

11.
Nat Genet ; 50(3): 381-389, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29483656

RESUMO

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.

12.
Nature ; 548(7665): 87-91, 2017 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-28746312

RESUMO

Hundreds of thousands of human genomes are now being sequenced to characterize genetic variation and use this information to augment association mapping studies of complex disorders and other phenotypic traits. Genetic variation is identified mainly by mapping short reads to the reference genome or by performing local assembly. However, these approaches are biased against discovery of structural variants and variation in the more complex parts of the genome. Hence, large-scale de novo assembly is needed. Here we show that it is possible to construct excellent de novo assemblies from high-coverage sequencing with mate-pair libraries extending up to 20 kilobases. We report de novo assemblies of 150 individuals (50 trios) from the GenomeDenmark project. The quality of these assemblies is similar to those obtained using the more expensive long-read technology. We use the assemblies to identify a rich set of structural variants including many novel insertions and demonstrate how this variant catalogue enables further deciphering of known association mapping signals. We leverage the assemblies to provide 100 completely resolved major histocompatibility complex haplotypes and to resolve major parts of the Y chromosome. Our study provides a regional reference genome that we expect will improve the power of future association mapping studies and hence pave the way for precision medicine initiatives, which now are being launched in many countries including Denmark.


Assuntos
Variação Genética/genética , Genética Populacional/normas , Genoma Humano/genética , Genômica/normas , Análise de Sequência de DNA/normas , Adulto , Alelos , Criança , Cromossomos Humanos Y/genética , Dinamarca , Feminino , Haplótipos/genética , Humanos , Complexo Principal de Histocompatibilidade/genética , Masculino , Idade Materna , Taxa de Mutação , Idade Paterna , Mutação Puntual/genética , Padrões de Referência
13.
Genetics ; 204(2): 711-722, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27535931

RESUMO

Denmark has played a substantial role in the history of Northern Europe. Through a nationwide scientific outreach initiative, we collected genetic and anthropometrical data from ∼800 high school students and used them to elucidate the genetic makeup of the Danish population, as well as to assess polygenic predictions of phenotypic traits in adolescents. We observed remarkable homogeneity across different geographic regions, although we could still detect weak signals of genetic structure reflecting the history of the country. Denmark presented genomic affinity with primarily neighboring countries with overall resemblance of decreasing weight from Britain, Sweden, Norway, Germany, and France. A Polish admixture signal was detected in Zealand and Funen, and our date estimates coincided with historical evidence of Wend settlements in the south of Denmark. We also observed considerably diverse demographic histories among Scandinavian countries, with Denmark having the smallest current effective population size compared to Norway and Sweden. Finally, we found that polygenic prediction of self-reported adolescent height in the population was remarkably accurate (R2 = 0.639 ± 0.015). The high homogeneity of the Danish population could render population structure a lesser concern for the upcoming large-scale gene-mapping studies in the country.


Assuntos
Demografia , Genética Populacional , Genômica , Adolescente , Antropometria , Dinamarca , Feminino , Genoma Humano , Humanos , Masculino , Densidade Demográfica
14.
Schizophr Bull ; 41(6): 1294-308, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25759474

RESUMO

Genome-wide association studies have identified multiple risk variants and loci that show robust association with schizophrenia. Nevertheless, it remains unclear how these variants confer risk to schizophrenia. In addition, the driving force that maintains the schizophrenia risk variants in human gene pool is poorly understood. To investigate whether expression-associated genetic variants contribute to schizophrenia susceptibility, we systematically integrated brain expression quantitative trait loci and genome-wide association data of schizophrenia using Sherlock, a Bayesian statistical framework. Our analyses identified ZNF323 as a schizophrenia risk gene (P = 2.22×10(-6)). Subsequent analyses confirmed the association of the ZNF323 and its expression-associated single nucleotide polymorphism rs1150711 in independent samples (gene-expression: P = 1.40×10(-6); single-marker meta-analysis in the combined discovery and replication sample comprising 44123 individuals: P = 6.85×10(-10)). We found that the ZNF323 was significantly downregulated in hippocampus and frontal cortex of schizophrenia patients (P = .0038 and P = .0233, respectively). Evidence for pleiotropic effects was detected (association of rs1150711 with lung function and gene expression of ZNF323 in lung: P = 6.62×10(-5) and P = 9.00×10(-5), respectively) with the risk allele (T allele) for schizophrenia acting as protective allele for lung function. Subsequent population genetics analyses suggest that the risk allele (T) of rs1150711 might have undergone recent positive selection in human population. Our findings suggest that the ZNF323 is a schizophrenia susceptibility gene whose expression may influence schizophrenia risk. Our study also illustrates a possible mechanism for maintaining schizophrenia risk variants in the human gene pool.


Assuntos
Proteínas de Ligação a DNA/genética , Lobo Frontal/metabolismo , Expressão Gênica/genética , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Pulmão/metabolismo , Locos de Características Quantitativas/genética , Esquizofrenia/genética , Seleção Genética/genética , Fatores de Transcrição/genética , Regulação para Baixo , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Risco
15.
Nat Commun ; 6: 5969, 2015 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-25597990

RESUMO

Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e-8 and 1.5e-9 per nucleotide per generation for SNVs and indels, respectively.


Assuntos
Genoma Humano/genética , Algoritmos , Humanos , Taxa de Mutação , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA/métodos
16.
BMC Evol Biol ; 14: 138, 2014 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-24947556

RESUMO

BACKGROUND: The two North Atlantic eel species, the European and the American eel, represent an ideal system in which to study parallel selection patterns due to their sister species status and the presence of ongoing gene flow. A panel of 80 coding-gene SNPs previously analyzed in American eel was used to genotype European eel individuals (glass eels) from 8 sampling locations across the species distribution. We tested for single-generation signatures of spatially varying selection in European eel by searching for elevated genetic differentiation using FST-based outlier tests and by testing for significant associations between allele frequencies and environmental variables. RESULTS: We found signatures of possible selection at a total of 11 coding-gene SNPs. Candidate genes for local selection constituted mainly genes with a major role in metabolism as well as defense genes. Contrary to what has been found for American eel, only 2 SNPs in our study correlated with differences in temperature, which suggests that other explanatory variables may play a role. None of the genes found to be associated with explanatory variables in European eel showed any correlations with environmental factors in the previous study in American eel. CONCLUSIONS: The different signatures of selection between species could be due to distinct selective pressures associated with the much longer larval migration for European eel relative to American eel. The lack of parallel selection in North Atlantic eels could also be due to most phenotypic traits being polygenic, thus reducing the likelihood of selection acting on the same genes in both species.


Assuntos
Enguias/classificação , Enguias/genética , Migração Animal , Animais , Enguias/crescimento & desenvolvimento , Enguias/fisiologia , Fluxo Gênico , Frequência do Gene , Interação Gene-Ambiente , Polimorfismo de Nucleotídeo Único
17.
Mol Ecol ; 22(9): 2424-40, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23551301

RESUMO

Little is known about how quickly natural populations adapt to changes in their environment and how temporal and spatial variation in selection pressures interact to shape patterns of genetic diversity. We here address these issues with a series of genome scans in four overfished populations of Atlantic cod (Gadus morhua) studied over an 80-year period. Screening of >1000 gene-associated single-nucleotide polymorphisms (SNPs) identified 77 loci that showed highly elevated levels of differentiation, likely as an effect of directional selection, in either time, space or both. Exploratory analysis suggested that temporal allele frequency shifts at certain loci may correlate with local temperature variation and with life history changes suggested to be fisheries induced. Interestingly, however, largely nonoverlapping sets of loci were temporal outliers in the different populations and outliers from the 1928 to 1960 period showed almost complete stability during later decades. The contrasting microevolutionary trajectories among populations resulted in sequential shifts in spatial outliers, with no locus maintaining elevated spatial differentiation throughout the study period. Simulations of migration coupled with observations of temporally stable spatial structure at neutral loci suggest that population replacement or gene flow alone could not explain all the observed allele frequency variation. Thus, the genetic changes are likely to at least partly be driven by highly dynamic temporally and spatially varying selection. These findings have important implications for our understanding of local adaptation and evolutionary potential in high gene flow organisms and underscore the need to carefully consider all dimensions of biocomplexity for evolutionarily sustainable management.


Assuntos
Evolução Molecular , Gadus morhua/genética , Polimorfismo de Nucleotídeo Único , Seleção Genética , Adaptação Fisiológica/genética , Animais , Meio Ambiente , Pesqueiros , Fluxo Gênico , Frequência do Gene , Genética Populacional , Genótipo , Dinâmica Populacional , Reprodutibilidade dos Testes , Análise de Sequência de DNA
18.
Eur J Hum Genet ; 20(1): 84-90, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21811305

RESUMO

Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride-sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using single-nucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population.


Assuntos
Canais Epiteliais de Sódio/genética , Estudo de Associação Genômica Ampla , Proteínas do Tecido Nervoso/genética , Transtorno de Pânico/genética , Canais Iônicos Sensíveis a Ácido , Alelos , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 17/genética , Canais de Sódio Degenerina , Dinamarca/epidemiologia , Dinamarca/etnologia , Grupos Étnicos/genética , Genótipo , Humanos , Repetições de Microssatélites , Transtorno de Pânico/diagnóstico , Transtorno de Pânico/epidemiologia , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética
19.
Acta Neuropsychiatr ; 24(2): 81-90, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26952950

RESUMO

OBJECTIVE: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression. METHOD: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro. RESULTS: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5%, n = 593; p = 0.009; odds ratio, OR: 1.46) as compared to ethnically matched controls (3.8%, n = 2912), while schizophrenia patients (4.1%, n = 503) did not differ. In vitro, the Pro7 substitution appeared to be associated with reduced levels of NPY without affecting its mRNA level. CONCLUSION: The Leu7Pro variation may increase the risk of major depression, possibly by affecting the biosynthesis of NPY.

20.
Mol Ecol ; 20(7): 1333-46, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21299662

RESUMO

European eels (Anguilla anguilla) spawn in the remote Sargasso Sea in partial sympatry with American eels (Anguilla rostrata), and juveniles are transported more than 5000 km back to the European and North African coasts. The two species have been regarded as classic textbook examples of panmixia, each comprising a single, randomly mating population. However, several recent studies based on continental samples have found subtle, but significant, genetic differentiation, interpreted as geographical or temporal heterogeneity between samples. Moreover, European and American eels can hybridize, but hybrids have been observed almost exclusively in Iceland, suggesting hybridization in a specific region of the Sargasso Sea and subsequent nonrandom dispersal of larvae. Here, we report the first molecular population genetics study based on analysis of 21 microsatellite loci in larvae of both Atlantic eel species sampled directly in the spawning area, supplemented by analysis of European glass eel samples. Despite a clear East-West gradient in the overlapping distribution of the two species in the Sargasso Sea, we only observed a single putative hybrid, providing evidence against the hypothesis of a wide marine hybrid zone. Analyses of genetic differentiation, isolation by distance, isolation by time and assignment tests provided strong evidence for panmixia in both the Sargasso Sea and across all continental samples of European eel after accounting for the presence of sibs among newly hatched larvae. European eel has declined catastrophically, and our findings call for management of the species as a single unit, necessitating coordinated international conservation efforts.


Assuntos
Anguilla/genética , Variação Genética , Hibridização Genética , Reprodução , Migração Animal , Animais , Repetições de Microssatélites , Oceanos e Mares
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