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1.
JAMA Psychiatry ; : 1-11, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31665216

RESUMO

Importance: Recurrent microdeletions and duplications in the genomic region 15q11.2 between breakpoints 1 (BP1) and 2 (BP2) are associated with neurodevelopmental disorders. These structural variants are present in 0.5% to 1.0% of the population, making 15q11.2 BP1-BP2 the site of the most prevalent known pathogenic copy number variation (CNV). It is unknown to what extent this CNV influences brain structure and affects cognitive abilities. Objective: To determine the association of the 15q11.2 BP1-BP2 deletion and duplication CNVs with cortical and subcortical brain morphology and cognitive task performance. Design, Setting, and Participants: In this genetic association study, T1-weighted brain magnetic resonance imaging were combined with genetic data from the ENIGMA-CNV consortium and the UK Biobank, with a replication cohort from Iceland. In total, 203 deletion carriers, 45 247 noncarriers, and 306 duplication carriers were included. Data were collected from August 2015 to April 2019, and data were analyzed from September 2018 to September 2019. Main Outcomes and Measures: The associations of the CNV with global and regional measures of surface area and cortical thickness as well as subcortical volumes were investigated, correcting for age, age2, sex, scanner, and intracranial volume. Additionally, measures of cognitive ability were analyzed in the full UK Biobank cohort. Results: Of 45 756 included individuals, the mean (SD) age was 55.8 (18.3) years, and 23 754 (51.9%) were female. Compared with noncarriers, deletion carriers had a lower surface area (Cohen d = -0.41; SE, 0.08; P = 4.9 × 10-8), thicker cortex (Cohen d = 0.36; SE, 0.07; P = 1.3 × 10-7), and a smaller nucleus accumbens (Cohen d = -0.27; SE, 0.07; P = 7.3 × 10-5). There was also a significant negative dose response on cortical thickness (ß = -0.24; SE, 0.05; P = 6.8 × 10-7). Regional cortical analyses showed a localization of the effects to the frontal, cingulate, and parietal lobes. Further, cognitive ability was lower for deletion carriers compared with noncarriers on 5 of 7 tasks. Conclusions and Relevance: These findings, from the largest CNV neuroimaging study to date, provide evidence that 15q11.2 BP1-BP2 structural variation is associated with brain morphology and cognition, with deletion carriers being particularly affected. The pattern of results fits with known molecular functions of genes in the 15q11.2 BP1-BP2 region and suggests involvement of these genes in neuronal plasticity. These neurobiological effects likely contribute to the association of this CNV with neurodevelopmental disorders.

2.
Mol Psychiatry ; 2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30705424

RESUMO

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

3.
Nat Commun ; 9(1): 3945, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30258056

RESUMO

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = -0.59, p-value = 3.14 × 10-6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.

4.
Addiction ; 113(11): 2073-2086, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30003630

RESUMO

BACKGROUND AND AIMS: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. METHODS: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. RESULTS: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19-60%]. Shared and unique environmental factors explained 39% (95% CI = 20-56%) and 22% (95% CI = 16-29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P < 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2  > 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. CONCLUSION: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders.

5.
Nat Commun ; 8: 13624, 2017 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-28098162

RESUMO

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.


Assuntos
Hipocampo/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Criança , Estudos de Coortes , Dipeptidil Peptidase 4/genética , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glicoproteínas/genética , Humanos , Masculino , Metionina Sulfóxido Redutases/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Tamanho do Órgão , Proteínas Serina-Treonina Quinases/genética , Adulto Jovem
6.
Int J Epidemiol ; 46(2): e19, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-27018016

RESUMO

The Saguenay Youth Study (SYS) is a two-generational study of adolescents and their parents (n = 1029 adolescents and 962 parents) aimed at investigating the aetiology, early stages and trans-generational trajectories of common cardiometabolic and brain diseases. The ultimate goal of this study is to identify effective means for increasing healthy life expectancy. The cohort was recruited from the genetic founder population of the Saguenay Lac St Jean region of Quebec, Canada. The participants underwent extensive (15-h) phenotyping, including an hour-long recording of beat-by-beat blood pressure, magnetic resonance imaging of the brain and abdomen, and serum lipidomic profiling with LC-ESI-MS. All participants have been genome-wide genotyped (with ∼ 8 M imputed single nucleotide polymorphisms) and a subset of them (144 adolescents and their 288 parents) has been genome-wide epityped (whole blood DNA, Infinium HumanMethylation450K BeadChip). These assessments are complemented by a detailed evaluation of each participant in a number of domains, including cognition, mental health and substance use, diet, physical activity and sleep, and family environment. The data collection took place during 2003-12 in adolescents (full) and their parents (partial), and during 2012-15 in parents (full). All data are available upon request.


Assuntos
Abdome/diagnóstico por imagem , Pressão Sanguínea , Encéfalo/diagnóstico por imagem , Cognição , Saúde Mental , Adolescente , Adulto , Estudos de Coortes , Feminino , Variação Genética , Humanos , Lipídeos/sangue , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Pais , Quebeque/epidemiologia , Transtornos Relacionados ao Uso de Substâncias
7.
Nat Neurosci ; 19(12): 1569-1582, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27694991

RESUMO

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.


Assuntos
Cognição/fisiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Grupo com Ancestrais do Continente Europeu , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Proteína Oncogênica v-akt/genética , Doença de Parkinson/genética , Fenótipo , Fosfatidilinositol 3-Quinases/genética
8.
Hum Mol Genet ; 24(20): 5733-45, 2015 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-26220975

RESUMO

DNA methylation may contribute to the etiology of complex genetic disorders through its impact on genome integrity and gene expression; it is modulated by DNA-sequence variants, named methylation quantitative trait loci (meQTLs). Most meQTLs influence methylation of a few CpG dinucleotides within short genomic regions (<3 kb). Here, we identified a layered genetic control of DNA methylation at numerous CpGs across a long 300 kb genomic region. This control involved a single long-range meQTL and multiple local meQTLs. The long-range meQTL explained up to 75% of variance in methylation of CpGs located over extended areas of the 300 kb region. The meQTL was identified in four samples (P = 2.8 × 10(-17), 3.1 × 10(-31), 4.0 × 10(-71) and 5.2 × 10(-199)), comprising a total of 2796 individuals. The long-range meQTL was strongly associated not only with DNA methylation but also with mRNA expression of several genes within the 300 kb region (P = 7.1 × 10(-18)-1.0 × 10(-123)). The associations of the meQTL with gene expression became attenuated when adjusted for DNA methylation (causal inference test: P = 2.4 × 10(-13)-7.1 × 10(-20)), indicating coordinated regulation of DNA methylation and gene expression. Further, the long-range meQTL was found to be in linkage disequilibrium with the most replicated locus of multiple sclerosis, a disease affecting primarily the brain white matter. In middle-aged adults free of the disease, we observed that the risk allele was associated with subtle structural properties of the brain white matter found in multiple sclerosis (P = 0.02). In summary, we identified a long-range meQTL that controls methylation and expression of several genes and may be involved in increasing brain vulnerability to multiple sclerosis.


Assuntos
Ilhas de CpG , Metilação de DNA , Regulação da Expressão Gênica , Predisposição Genética para Doença , Esclerose Múltipla/genética , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Alelos , Cromossomos Humanos Par 6 , Feminino , Genômica , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
9.
Int J Hypertens ; 2015: 734586, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25692033

RESUMO

Adolescents who exhibit exaggerated blood pressure (BP) reactivity to physical and mental challenges are at increased risk of developing hypertension in adulthood. BP at rest and in response to challenges is higher in males than females, beginning in early adolescence. CYP17A1 is one of the well-established gene loci of adult hypertension. Here, we investigated whether this gene locus is associated with elevated BP at rest and in response to physical (active standing) and mental (math stress) challenges in adolescence. We studied 496 male and 532 female adolescents (age 12-18 years) who were recruited from a genetic founder population. Our results showed that the variant of CYP17A1 rs10786718 was associated with enhanced BP reactivity to the mental but not physical challenge and in males but not females. In males, BP increase in response to math stress was higher in major versus minor allele homozygotes by 7.6 mm Hg (P = 8.3 × 10(-6)). Resting BP was not associated with the CYP17A1 variant in either sex. These results suggest that, in adolescent males but not females, CYP17A1 enhances BP reactivity to mental stress. Whether this effect contributes to the higher prevalence of hypertension in males than females later in life remains to be determined.

10.
Nature ; 520(7546): 224-9, 2015 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-25607358

RESUMO

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.


Assuntos
Encéfalo/anatomia & histologia , Variação Genética/genética , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Apoptose/genética , Núcleo Caudado/anatomia & histologia , Criança , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Loci Gênicos/genética , Hipocampo/anatomia & histologia , Humanos , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Tamanho do Órgão/genética , Putamen/anatomia & histologia , Caracteres Sexuais , Crânio/anatomia & histologia , Adulto Jovem
11.
Hum Mol Genet ; 22(5): 1050-8, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23201753

RESUMO

Genetic variations in fat mass- and obesity (FTO)-associated gene, a well-replicated gene locus of obesity, appear to be associated also with reduced regional brain volumes in elderly. Here, we examined whether FTO is associated with total brain volume in adolescence, thus exploring possible developmental effects of FTO. We studied a population-based sample of 598 adolescents recruited from the French Canadian founder population in whom we measured brain volume by magnetic resonance imaging. Total fat mass was assessed with bioimpedance and body mass index was determined with anthropometry. Genotype-phenotype associations were tested with Merlin under an additive model. We found that the G allele of FTO (rs9930333) was associated with higher total body fat [TBF (P = 0.002) and lower brain volume (P = 0.005)]. The same allele was also associated with higher lean body mass (P = 0.03) and no difference in height (P = 0.99). Principal component analysis identified a shared inverse variance between the brain volume and TBF, which was associated with FTO at P = 5.5 × 10(-6). These results were replicated in two independent samples of 413 and 718 adolescents, and in a meta-analysis of all three samples (n = 1729 adolescents), FTO was associated with this shared inverse variance at P = 1.3 × 10(-9). Co-expression networks analysis supported the possibility that the underlying FTO effects may occur during embryogenesis. In conclusion, FTO is associated with shared inverse variance between body adiposity and brain volume, suggesting that this gene may exert inverse effects on adipose and brain tissues. Given the completion of the overall brain growth in early childhood, these effects may have their origins during early development.


Assuntos
Encéfalo/anatomia & histologia , Obesidade/genética , Proteínas/genética , Tecido Adiposo/metabolismo , Adiposidade/genética , Adolescente , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Antropometria , Índice de Massa Corporal , Encéfalo/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Obesidade/metabolismo , Proteínas/metabolismo
12.
Nat Genet ; 44(5): 552-61, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22504417

RESUMO

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).


Assuntos
Encéfalo/fisiopatologia , Cromossomos Humanos Par 12/genética , Hipocampo/fisiopatologia , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Loci Gênicos , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto
13.
J Clin Endocrinol Metab ; 97(1): E145-50, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22013104

RESUMO

CONTEXT: Hypertension, typically considered a disorder of adulthood, is now emerging in adolescence. This is mainly due to the growing prevalence of obesity and the fact that excess body fat increases blood pressure (BP). OBJECTIVE: The objective of the study was to investigate whether genome-wide identified gene loci of obesity are associated with elevated BP in adolescence. DESIGN: This was a genotype-phenotype association study. SETTING: The study was conducted in a French-Canadian founder population. PARTICIPANTS: Participants included 598 adolescents, aged 12-18 yr. INTERVENTION: Testing associations between 530,011 single-nucleotide polymorphisms (SNP; Human610W-Quad BeadChip) and obesity measures and between identified SNP and BP. PRIMARY OUTCOME MEASURES: Total fat mass (TFM) was assessed with bioelectrical impedance, and body mass index (BMI) was determined with anthropometry. BP was measured beat by beat during an hour-long protocol. RESULTS: The genome-wide association studies of TFM and BMI revealed two novel and several previously identified loci of obesity. The former were PAX5 (rs16933812, TFM: P = 9.3 × 10(-9)) and MRPS22 (rs7638110, BMI: P = 4.6 × 10(-8)), and the top ones among the latter (P < 5 × 10(-4)) were MC4R (rs17773430, BMI: P = 5.8 × 10(-6)), FTO (rs9930333, BMI: P = 1.9 × 10(-4)), and MTCH2 (rs7120548, BMI: P = 1.9 × 10(-4)). From these five, only the PAX5, MRPS22, and FTO were also associated with BP; their minor allele homozygotes vs. major allele homozygotes showed greater TFM by 2.9-8.0 kg and higher BP by 3.3-6.7 mm Hg. CONCLUSIONS: Genome-wide association studies conducted in an adolescent founder population revealed two new and a number of previously identified loci of obesity and demonstrated that several but not all of these loci are also associated with elevated BP. These results begin to reveal the genetic architecture of obesity-induced hypertension.


Assuntos
Pressão Sanguínea/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Obesidade/genética , Adolescente , Idade de Início , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Canadá/epidemiologia , Criança , Mapeamento Cromossômico , Feminino , Loci Gênicos/genética , Loci Gênicos/fisiologia , Predisposição Genética para Doença , Humanos , Hipertensão/complicações , Hipertensão/genética , Masculino , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/fisiopatologia , Quebeque/epidemiologia , Estudos de Validação como Assunto
14.
Cereb Cortex ; 22(11): 2634-42, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22156575

RESUMO

The most dramatic growth of the human brain occurs in utero and during the first 2 years of postnatal life. Genesis of the cerebral cortex involves cell proliferation, migration, and apoptosis, all of which may be influenced by prenatal environment. Here, we show that variation in KCTD8 (potassium channel tetramerization domain 8) is associated with brain size in female adolescents (rs716890, P = 5.40 × 10(-09)). Furthermore, we found that the KCTD8 locus interacts with prenatal exposure to maternal cigarette smoking vis-à-vis cortical area and cortical folding: In exposed girls only, the KCTD8 locus explains up to 21% of variance. Using head circumference as a proxy of brain size at 7 years of age, we have replicated this gene-environment interaction in an independent sample. We speculate that KCTD8 might modulate adverse effects of smoking during pregnancy on brain development via apoptosis triggered by low intracellular levels of potassium, possibly reducing the number of progenitor cells.


Assuntos
Encéfalo/crescimento & desenvolvimento , Retardo do Crescimento Fetal/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar/efeitos adversos , Adolescente , Adulto , Algoritmos , Animais , Peso ao Nascer/fisiologia , Estatura/fisiologia , Encéfalo/embriologia , Canadá/epidemiologia , Córtex Cerebral/anatomia & histologia , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Idade Gestacional , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imagem por Ressonância Magnética , Camundongos , Pais , Gravidez , Complicações na Gravidez/genética
15.
Hum Brain Mapp ; 28(6): 502-18, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17469173

RESUMO

The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large-scale study of gene-environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long-term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individual's response to an in utero environment (i.e. PEMCS), the study is family-based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac-Saint-Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome-wide scan will be carried out with sib-pair linkage analyses, and fine mapping of identified loci will be done with family-based association analyses. Adolescent sibships (12-18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French-Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer-based neuropsychological tests, (3) hospital-based cardiovascular, body-composition and metabolic assessments, and (4) questionnaire-derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home-environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI-based assessment of familiality in the brain size and the volumes of grey and white matter.


Assuntos
Mapeamento Encefálico , Encéfalo , Família , Corpo Humano , Comportamento Materno/psicologia , Fumar , Adolescente , Pressão Sanguínea/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Estudos de Casos e Controles , Criança , Estudos Transversais , Ácidos Graxos/metabolismo , Feminino , Inquéritos Epidemiológicos , Frequência Cardíaca/fisiologia , Humanos , Rim/fisiologia , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Gravidez , Estudos Retrospectivos , Fumar/fisiopatologia
16.
Hypertension ; 46(6): 1280-5, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16216983

RESUMO

Essential hypertension is a heterogeneous disorder that is thought to develop because of several overlapping subsets of underlying mechanisms. One such causal pathway may involve pathophysiological alterations induced by obesity. In the present study, we examined whether investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, facilitates the search for its genes. Fifty-five extended families were selected on the basis of having > or =2 siblings affected by hypertension from a geographically remote French-Canadian population. Fifteen of these families showed a high prevalence (> or =70%) of obesity. Genome-wide scan using qualitative multipoint linkage analysis (GeneHunter 2.1; marker density <10 cM) was performed in the entire set of hypertensive families and the subset with high prevalence of obesity. In the scan involving all 55 families, the most significant loci (logarithm of odds [LOD] score=2.5) were identified on chromosomes 1 (D1S1597) and 11 (D11S1999). In the scan including only the subset of families with obesity-hypertension, the most significant locus (LOD score=3.1) was found on chromosome 1 in the same region as the scan involving all families (D1S1597). Genotyping additional markers increased the significance of this locus (LOD score=3.5) and refined its position (D1S2672). Several candidate genes of obesity-hypertension are located in close proximity; these include the tumor necrosis factor receptor 2 and atrial natriuretic peptide genes. These results suggest that investigating clinically defined subtypes of hypertension, such as obesity-associated hypertension, may facilitate the search for genes of this complex disorder.


Assuntos
Ligação Genética , Genoma Humano , Hipertensão/genética , Obesidade/genética , Fator Natriurético Atrial/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 11 , Feminino , França/etnologia , Genótipo , Humanos , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade , Obesidade/etnologia , Linhagem , Quebeque , Receptores Tipo II do Fator de Necrose Tumoral/genética
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