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1.
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
2.
Cell ; 167(5): 1369-1384.e19, 2016 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-27863249

RESUMO

Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.


Assuntos
Células Sanguíneas/citologia , Doença/genética , Regiões Promotoras Genéticas , Linhagem da Célula , Separação Celular , Cromatina , Elementos Facilitadores Genéticos , Epigenômica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hematopoese , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
3.
Nat Commun ; 7: 13555, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27898055

RESUMO

The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.


Assuntos
Metilação de DNA/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Ilhas de CpG/genética , Sangue Fetal/metabolismo , Humanos , Anotação de Sequência Molecular , Fatores de Tempo , Gêmeos Monozigóticos/genética
4.
PLoS One ; 10(7): e0131202, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26176695

RESUMO

Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.


Assuntos
Síndrome de Asperger/genética , Polimorfismo de Nucleotídeo Único , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino
5.
PLoS Genet ; 10(7): e1004494, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25078778

RESUMO

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻8) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹7). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻4), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.


Assuntos
Efeito Fundador , Doenças Genéticas Inatas , Deriva Genética , Genética Populacional , Grupo com Ancestrais do Continente Europeu , Exoma/genética , Feminino , Finlândia , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fenótipo
6.
Nat Genet ; 46(9): 944-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25086666

RESUMO

Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Mutação , Exoma , Feminino , Código Genético , Predisposição Genética para Doença , Genética Médica/métodos , Humanos , Masculino
7.
PLoS One ; 9(5): e96374, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24801482

RESUMO

Mathematical ability is heritable, but few studies have directly investigated its molecular genetic basis. Here we aimed to identify specific genetic contributions to variation in mathematical ability. We carried out a genome wide association scan using pooled DNA in two groups of U.K. samples, based on end of secondary/high school national academic exam achievement: high (n = 419) versus low (n = 183) mathematical ability while controlling for their verbal ability. Significant differences in allele frequencies between these groups were searched for in 906,600 SNPs using the Affymetrix GeneChip Human Mapping version 6.0 array. After meeting a threshold of p<1.5×10(-5), 12 SNPs from the pooled association analysis were individually genotyped in 542 of the participants and analyzed to validate the initial associations (lowest p-value 1.14 ×10(-6)). In this analysis, one of the SNPs (rs789859) showed significant association after Bonferroni correction, and four (rs10873824, rs4144887, rs12130910 rs2809115) were nominally significant (lowest p-value 3.278 × 10(-4)). Three of the SNPs of interest are located within, or near to, known genes (FAM43A, SFT2D1, C14orf64). The SNP that showed the strongest association, rs789859, is located in a region on chromosome 3q29 that has been previously linked to learning difficulties and autism. rs789859 lies 1.3 kbp downstream of LSG1, and 700 bp upstream of FAM43A, mapping within the potential promoter/regulatory region of the latter. To our knowledge, this is only the second study to investigate the association of genetic variants with mathematical ability, and it highlights a number of interesting markers for future study.


Assuntos
Transtorno Autístico/genética , Cromossomos Humanos Par 3/genética , Transtornos de Aprendizagem/genética , Locos de Características Quantitativas/genética , Adolescente , Mapeamento Cromossômico/métodos , Feminino , Frequência do Gene/genética , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Matemática/métodos , Polimorfismo de Nucleotídeo Único/genética
8.
Am J Hum Genet ; 93(4): 607-19, 2013 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-24094742

RESUMO

Copy number variation (CNV) is an important determinant of human diversity and plays important roles in susceptibility to disease. Most studies of CNV carried out to date have made use of chromosome microarray and have had a lower size limit for detection of about 30 kilobases (kb). With the emergence of whole-exome sequencing studies, we asked whether such data could be used to reliably call rare exonic CNV in the size range of 1-30 kilobases (kb), making use of the eXome Hidden Markov Model (XHMM) program. By using both transmission information and validation by molecular methods, we confirmed that small CNV encompassing as few as three exons can be reliably called from whole-exome data. We applied this approach to an autism case-control sample (n = 811, mean per-target read depth = 161) and observed a significant increase in the burden of rare (MAF ≤1%) 1-30 kb CNV, 1-30 kb deletions, and 1-10 kb deletions in ASD. CNV in the 1-30 kb range frequently hit just a single gene, and we were therefore able to carry out enrichment and pathway analyses, where we observed enrichment for disruption of genes in cytoskeletal and autophagy pathways in ASD. In summary, our results showed that XHMM provided an effective means to assess small exonic CNV from whole-exome data, indicated that rare 1-30 kb exonic deletions could contribute to risk in up to 7% of individuals with ASD, and implicated a candidate pathway in developmental delay syndromes.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Variações do Número de Cópias de DNA , Exoma , Autofagia/genética , Sequência de Bases , Estudos de Casos e Controles , Criança , Éxons , Deleção de Genes , Predisposição Genética para Doença , Humanos , Dados de Sequência Molecular , Análise de Sequência de DNA/métodos
9.
Nat Neurosci ; 16(9): 1228-1237, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23912948

RESUMO

Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3ß revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3ß to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3ß in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.


Assuntos
Anormalidades Múltiplas/genética , Transtornos Cognitivos/genética , DNA Topoisomerases Tipo I/genética , Síndrome de DiGeorge/genética , Esquizofrenia/genética , Deleção de Sequência/genética , Adolescente , Adulto , Idoso , Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Transtornos Cognitivos/epidemiologia , Estudos de Coortes , Saúde da Família , Feminino , Finlândia/epidemiologia , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Perfilação da Expressão Gênica , Estudos de Associação Genética , Genótipo , Células HEK293 , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Proteínas/genética , Proteínas/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Esquizofrenia/epidemiologia , Adulto Jovem
10.
PLoS One ; 8(3): e58552, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23505534

RESUMO

Several studies examined the fine-scale structure of human genetic variation in Europe. However, the European sets analyzed represent mainly northern, western, central, and southern Europe. Here, we report an analysis of approximately 166,000 single nucleotide polymorphisms in populations from eastern (northeastern) Europe: four Russian populations from European Russia, and three populations from the northernmost Finno-Ugric ethnicities (Veps and two contrast groups of Komi people). These were compared with several reference European samples, including Finns, Estonians, Latvians, Poles, Czechs, Germans, and Italians. The results obtained demonstrated genetic heterogeneity of populations living in the region studied. Russians from the central part of European Russia (Tver, Murom, and Kursk) exhibited similarities with populations from central-eastern Europe, and were distant from Russian sample from the northern Russia (Mezen district, Archangelsk region). Komi samples, especially Izhemski Komi, were significantly different from all other populations studied. These can be considered as a second pole of genetic diversity in northern Europe (in addition to the pole, occupied by Finns), as they had a distinct ancestry component. Russians from Mezen and the Finnic-speaking Veps were positioned between the two poles, but differed from each other in the proportions of Komi and Finnic ancestries. In general, our data provides a more complete genetic map of Europe accounting for the diversity in its most eastern (northeastern) populations.


Assuntos
Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Variação Genética , Estudo de Associação Genômica Ampla , Análise por Conglomerados , Europa (Continente) , Genética Populacional , Genótipo , Geografia , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Federação Russa
11.
Eur J Hum Genet ; 21(6): 659-65, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23249956

RESUMO

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 >145000 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.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Variação Genética , Genética Populacional , Análise por Conglomerados , Genoma Humano/genética , Homozigoto , Humanos , Itália , Desequilíbrio de Ligação/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética
12.
PLoS Genet ; 8(3): e1002563, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22438818

RESUMO

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)  =  11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n  =  19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN)  =  3.01E-05, p(ICBP-GWAS)  =  0.0007, p(ALL)  =  8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.


Assuntos
Pressão Sanguínea , Estudo de Associação Genômica Ampla , Aneurisma Intracraniano/genética , Dedos de Zinco/genética , Adulto , Pressão Sanguínea/genética , Cromossomos Humanos Par 5/genética , Estudos de Coortes , Feminino , Finlândia , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Miócitos de Músculo Liso/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Fatores de Transcrição/genética
13.
PLoS One ; 6(8): e22547, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21829632

RESUMO

Patterns of genetic diversity have previously been shown to mirror geography on a global scale and within continents and individual countries. Using genome-wide SNP data on 5174 Swedes with extensive geographical coverage, we analyzed the genetic structure of the Swedish population. We observed strong differences between the far northern counties and the remaining counties. The population of Dalarna county, in north middle Sweden, which borders southern Norway, also appears to differ markedly from other counties, possibly due to this county having more individuals with remote Finnish or Norwegian ancestry than other counties. An analysis of genetic differentiation (based on pairwise F(st)) indicated that the population of Sweden's southernmost counties are genetically closer to the HapMap CEU samples of Northern European ancestry than to the populations of Sweden's northernmost counties. In a comparison of extended homozygous segments, we detected a clear divide between southern and northern Sweden with small differences between the southern counties and considerably more segments in northern Sweden. Both the increased degree of homozygosity in the north and the large genetic differences between the south and the north may have arisen due to a small population in the north and the vast geographical distances between towns and villages in the north, in contrast to the more densely settled southern parts of Sweden. Our findings have implications for future genome-wide association studies (GWAS) with respect to the matching of cases and controls and the need for within-county matching. We have shown that genetic differences within a single country may be substantial, even when viewed on a European scale. Thus, population stratification needs to be accounted for, even within a country like Sweden, which is often perceived to be relatively homogenous and a favourable resource for genetic mapping, otherwise inferences based on genetic data may lead to false conclusions.


Assuntos
Genética Populacional , Haplótipos , Homozigoto , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , Suécia
14.
Hum Mol Genet ; 20(13): 2686-95, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21505072

RESUMO

Phenotype mining is a novel approach for elucidating the genetic basis of complex phenotypic variation. It involves a search of rich phenotype databases for measures correlated with genetic variation, as identified in genome-wide genotyping or sequencing studies. An initial implementation of phenotype mining in a prospective unselected population cohort, the Northern Finland 1966 Birth Cohort (NFBC1966), identifies neurodevelopment-related traits-intellectual deficits, poor school performance and hearing abnormalities-which are more frequent among individuals with large (>500 kb) deletions than among other cohort members. Observation of extensive shared single nucleotide polymorphism haplotypes around deletions suggests an opportunity to expand phenotype mining from cohort samples to the populations from which they derive.


Assuntos
Variações do Número de Cópias de DNA/genética , Mineração de Dados , Estudos de Associação Genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Bases de Dados Factuais , Feminino , Finlândia , Deriva Genética , Genética Populacional , Haplótipos , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único/genética , Deleção de Sequência/genética , Adulto Jovem
15.
Autism Res ; 4(3): 228-33, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21384559

RESUMO

About 80% of cases with autism express intellectual disability. Both in autism and in mental retardation without autism the majority of the cases are males, suggesting a X-chromosomal effect. In fact, some molecular evidence has been obtained for a common genetic background for autism spectrum disorders (ASD) and X-linked mental retardation (XLMR). In several genome-wide scans (GWS), evidence for linkage at X-chromosome has been reported including the GWS of Finnish ASD families with the highest multipoint lod score (MLS) of 2.75 obtained close to DXS7132 at Xq11.1. To further dissect the relationship between autism and genes implicated in XLMR, we have fine-mapped Xq11.1-q21.33 and analyzed five candidate genes in the region. We refined the region using 26 microsatellite markers and linkage analysis in 99 Finnish families with ASD. The most significant evidence for linkage was observed at DXS1225 on Xq21.1 with a nonparametric multipoint NPL(all) value of 3.43 (P = 0.0004). We sequenced the coding regions and splice sites of RPS6KA6 and ZNF711 residing at the peak region in 42 male patients from families contributing to the linkage. We also analyzed ACSL4 and DLG3, which have previously been known to cause XLMR and IL1RAPL2, a homologous gene for IL1RAPL1 that is mutated in autism and XLMR. A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Mapeamento Cromossômico , Cromossomos Humanos X/genética , Coenzima A Ligases/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Testes Genéticos , Proteína Acessória do Receptor de Interleucina-1/genética , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas Nucleares/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Aberrações dos Cromossomos Sexuais , Fatores de Transcrição/genética , Adolescente , Alelos , Síndrome de Asperger/genética , Criança , Pré-Escolar , Feminino , Finlândia , Estudos de Associação Genética , Ligação Genética , Genótipo , Humanos , Lactente , Escore Lod , Masculino , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genética
16.
PLoS One ; 4(5): e5472, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19424496

RESUMO

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 (lambda) (ranging from 1.00 to 4.21), fixation index (F(st)) (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).


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Polimorfismo de Nucleotídeo Único/genética , Europa (Continente)/etnologia , Frequência do Gene , Marcadores Genéticos , Genoma Humano/genética , Humanos , Desequilíbrio de Ligação/genética , Análise de Componente Principal
17.
Hum Mol Genet ; 18(15): 2912-21, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19454485

RESUMO

Population isolates, such as Finland, have proved beneficial in mapping rare causative genetic variants due to a limited number of founders resulting in reduced genetic heterogeneity and extensive linkage disequilibrium (LD). We have here used this special opportunity to identify rare alleles in autism by genealogically tracing 20 autism families into one extended pedigree with verified genealogical links reaching back to the 17th century. In this unique pedigree, we performed a dense microsatellite marker genome-wide scan of linkage and LD and followed initial findings with extensive fine-mapping. We identified a putative autism susceptibility locus at 19p13.3 and obtained further evidence for previously identified loci at 1q23 and 15q11-q13. Most promising candidate genes were TLE2 and TLE6 clustered at 19p13 and ATP1A2 at 1q23.


Assuntos
Transtorno Autístico/genética , Estudo de Associação Genômica Ampla , Desequilíbrio de Ligação , Linhagem , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 19/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Finlândia , Humanos , Masculino , Repetições de Microssatélites
18.
Am J Med Genet B Neuropsychiatr Genet ; 150B(5): 741-6, 2009 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-19035560

RESUMO

Autism spectrum disorders (ASDs) are severe neurodevelopmental disorders with a strong genetic component. Only a few predisposing genes have been identified so far. We have previously performed a genome-wide linkage screen for ASDs in Finnish families where the most significant linkage peak was identified at 3q25-27. Here, 11 positional and functionally relevant candidate genes at 3q25-27 were tested for association with autistic disorder. Genotypes of 125 single nucleotide polymorphisms (SNPs) were determined in 97 families with at least one individual affected with autistic disorder. The most significant association was observed using two non-synonymous SNPs in HTR3C, rs6766410 and rs6807362, both resulting in P = 0.0012 in family-based association analysis. In addition, the haplotype C-C corresponding to amino acids N163-A405 was overtransmitted to affected individuals (P = 0.006). Sequencing revealed no other variants in the coding region or splice sites of HTR3C. Based on the association analysis results in a previously identified linkage region, we propose that HTR3C represents a novel candidate locus for ASDs and should be tested in other populations.


Assuntos
Transtorno Autístico/genética , Polimorfismo de Nucleotídeo Único , Receptores 5-HT3 de Serotonina/genética , Alelos , Família , Finlândia , Frequência do Gene , Ligação Genética , Predisposição Genética para Doença , Genótipo , Humanos
19.
Am J Hum Genet ; 83(6): 787-94, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19061986

RESUMO

Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulations.


Assuntos
Efeito Fundador , Variação Genética , Genoma Humano , Desequilíbrio de Ligação , População , Alelos , Cromossomos Humanos Par 22 , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Homozigoto , Humanos , Polimorfismo de Nucleotídeo Único
20.
Autism Res ; 1(3): 189-92, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19360665

RESUMO

Two single nucleotide polymorphisms (SNP) within Mitochondrial Aspartate/Glutamate Carrier SLC25A12 gene have recently shown to be strongly associated with autism. Here, we attempted to replicate this finding in two separate Finnish samples with autism spectrum disorders. Family-based association analysis of two SNPs, rs2056202 and rs2292813, previously shown to be associated with autism was performed in two samples with different phenotypic characteristics. The samples included 97 families with strictly defined autism and 29 extended families with Asperger syndrome (AS). We detected association at rs2292813 (FBAT, P=0.0018) in the Finnish autism sample. In, addition other family-based analysis methods supported this finding. By contrast, analysis of the AS sample yielded no evidence for association. This study shows further support that genetic variants within SLC25A12 gene contribute to the etiology of autism.


Assuntos
Transtorno Autístico/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Adulto , Síndrome de Asperger/genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
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