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1.
Animal ; 13(8): 1736-1743, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30614437

RESUMO

There is absence knowledge about the effects of lactation trimester and parity on eating behavior, production and efficiency of dairy cows. Objective of this study was to identify and characterize in 340 dairy cows, the 20% high efficient (HE), 20% low efficient (LE) and 60% mid efficient (ME) cows according to their individual residual feed intake (RFI) values, within and between lactation trimesters and between 1st and 2nd parities. Efficiency effect within each lactation trimester, was exhibited in daily dry matter intake (DMI), eating rate and meal size, that were the highest in LE cows, moderate in the ME cows and lowest in the HE group. Daily eating time, meal frequency, yields of milk and energy-corrected milk (ECM) and BW were similar in the three efficiency groups within each trimester. The lower efficiency of the LE cows in each trimester attributes to their larger metabolic energy intake, heat production and energy losses. In subgroup of 52 multiparous cows examined along their 1st and 2nd trimesters, milk and ECM production, DMI, eating behavior and efficiency traits were similar with high Pearson's correlation (r=0.78 to 0.89) between trimesters. In another subgroup of 42 multiparous cows measured at their 2nd and 3rd trimesters, milk and ECM yield, DMI and eating time were reduced (P<0.01) at the 3rd trimester, but eating rate, meal frequency and meal size remained similar with high Pearson's correlation (r=0.74 to 0.88) between trimesters. In subgroup of 26 cows measured in 1st and 2nd parities, DMI, BW, milk and ECM yield, and ECM/DMI increased in the 2nd lactation, but eating behavior and RFI traits were similar in both parities. These findings encourage accurate prediction of DMI based on a model that includes eating behavior parameters, together with individual measurement of ECM production. This can be further used to identify HE cows in commercial herd, a step necessary for potential genetic selection program aimed to improve herd efficiency.

2.
J Dairy Sci ; 101(12): 10973-10984, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30268615

RESUMO

This study aimed to identify individual characteristics differing among high-efficiency (HEf; upper 20%, n = 31), low-efficiency (LEf; lower 20%, n = 31), and mid-efficiency (MEf, 60% n = 93) lactating cows. Primiparous (37) and multiparous (118) high-producing milking cows at 30 to 180 d in milk were fed individually a low-roughage diet [31.6% of dry matter (DM)] for 4 wk. Daily average DM intake, rate of eating, visit duration, meal size, and daily rumination time were higher in LEf compared with HEf cows. On the other hand, HEf cows exhibited higher digestibility of DM, crude protein, and neutral detergent fiber than the LEf cows. Daily eating time was similar in the HEf and LEf groups and higher than that of the MEf cows. Visit and meal frequency, average visit and meal duration, daily lying time, and pedometer activity were similar in the HEf, LEf, and MEf groups. The HEf cows produced 1.75% more milk, but similar energy-corrected milk compared with the LEf cows. Milk fat and protein content were lower by 1.8 and 3.8%, respectively, in the HEf cows than in the LEf group. Body weight (BW) and BW gain were similar in the 3 efficiency groups. Diurnal distribution of DM intake showed 6 distinct major meals, each composed of 1.1 to 1.6 visits. Higher intake peaks (greater meal size) were found in the LEf cows compared with the HEf group. Daily DM intake was highly correlated (affected) with energy-corrected milk production (r = 0.61), BW (r = 0.4), eating rate (r = 0.57), and visit size (r = 0.54). Energy balance showed that the lower efficiency of the LEf cows was attributed to their excess heat production and energy loss.

3.
Transl Psychiatry ; 7(10): e1249, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29064472

RESUMO

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophrenia N=230, schizoaffective disorder N=155, psychotic bipolar disorder N=206 and healthy controls N=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism in IPO8 (12p11.21, P=8 × 10-11), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs in SH3GL2 (9p22.2, P=3 × 10-8). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs in PCDH12 (5q31.3, P=1.6 × 10-10), and suggestive associations were observed with NRSN1 (6p22.3, P=5.4 × 10-8) and LMO7 (13q22.2, P=7.3x10-8), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10-9). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10-2-9.8 × 10-4). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.


Assuntos
Transtornos Psicóticos/genética , Transtornos Psicóticos/fisiopatologia , Acompanhamento Ocular Uniforme , Movimentos Sacádicos , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/complicações , Esquizofrenia/complicações , Esquizofrenia/genética , Esquizofrenia/fisiopatologia
4.
Psychol Med ; 45(7): 1379-88, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25399360

RESUMO

BACKGROUND: Findings from family and twin studies support a genetic contribution to the development of sexual orientation in men. However, previous studies have yielded conflicting evidence for linkage to chromosome Xq28. METHOD: We conducted a genome-wide linkage scan on 409 independent pairs of homosexual brothers (908 analyzed individuals in 384 families), by far the largest study of its kind to date. RESULTS: We identified two regions of linkage: the pericentromeric region on chromosome 8 (maximum two-point LOD = 4.08, maximum multipoint LOD = 2.59), which overlaps with the second strongest region from a previous separate linkage scan of 155 brother pairs; and Xq28 (maximum two-point LOD = 2.99, maximum multipoint LOD = 2.76), which was also implicated in prior research. CONCLUSIONS: Results, especially in the context of past studies, support the existence of genes on pericentromeric chromosome 8 and chromosome Xq28 influencing development of male sexual orientation.


Assuntos
Cromossomos Humanos Par 8/genética , Cromossomos Humanos X/genética , Ligação Genética/genética , Estudo de Associação Genômica Ampla , Homossexualidade Masculina/genética , Adulto , Humanos , Masculino , Irmãos , Estados Unidos
5.
Mol Psychiatry ; 19(2): 175-83, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23337943

RESUMO

The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially expressed in transgenic mice compared with wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Motivação/fisiologia , Reflexo de Sobressalto/fisiologia , Comportamento Estereotipado/fisiologia , Processamento Alternativo , Animais , Encéfalo/metabolismo , Células COS , Cercopithecus aethiops , Feminino , Preferências Alimentares/fisiologia , Humanos , Masculino , Transtornos Mentais/genética , Camundongos , Camundongos Transgênicos , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Especificidade da Espécie , Testículo/metabolismo , Transcriptoma
6.
Mol Psychiatry ; 19(8): 890-4, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23979604

RESUMO

Timothy Syndrome (TS) is caused by very rare exonic mutations of the CACNA1C gene that produce delayed inactivation of Cav1.2 voltage-gated calcium channels during cellular action potentials, with greatly increased influx of calcium into the activated cells. The major clinical feature of this syndrome is a long QT interval that results in cardiac arrhythmias. However, TS also includes cognitive impairment, autism and major developmental delays in many of the patients. We observed the appearance of bipolar disorder (BD) in a patient with a previously reported case of TS, who is one of the very few patients to survive childhood. This is most interesting because the common single-nucleotide polymorphism (SNP) most highly associated with BD is rs1006737, which we show here is a cis-expression quantitative trait locus for CACNA1C in human cerebellum, and the risk allele (A) is associated with decreased expression. To combine the CACNA1C perturbations in the presence of BD in this patient and in patients with the common CACNA1C SNP risk allele, we would propose that either increase or decrease in calcium influx in excitable cells can be associated with BD. In treatment of BD with calcium channel blocking drugs, we would predict better response in patients without the risk allele, because they have increased CACNA1C expression.


Assuntos
Transtorno Bipolar/genética , Encéfalo/metabolismo , Canais de Cálcio Tipo L/genética , Regulação para Baixo/genética , Predisposição Genética para Doença/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Transtorno Autístico , Transtorno Bipolar/complicações , Canais de Cálcio Tipo L/biossíntese , Cerebelo/metabolismo , Perfilação da Expressão Gênica , Humanos , Síndrome do QT Longo/complicações , Síndrome do QT Longo/genética , Masculino , Lobo Parietal/metabolismo , Locos de Características Quantitativas/genética , Sindactilia/complicações , Sindactilia/genética
9.
Mol Psychiatry ; 18(12): 1308-14, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23147385

RESUMO

Schizophrenia (SCZ) and bipolar disorder (BD) are highly heritable psychiatric disorders. Associated genetic and gene expression changes have been identified, but many have not been replicated and have unknown functions. We identified groups of genes whose expressions varied together, that is co-expression modules, then tested them for association with SCZ. Using weighted gene co-expression network analysis, we show that two modules were differentially expressed in patients versus controls. One, upregulated in cerebral cortex, was enriched with neuron differentiation and neuron development genes, as well as disease genome-wide association study genetic signals; the second, altered in cerebral cortex and cerebellum, was enriched with genes involved in neuron protection functions. The findings were preserved in five expression data sets, including sets from three brain regions, from a different microarray platform, and from BD patients. From those observations, we propose neuron differentiation and development pathways may be involved in etiologies of both SCZ and BD, and neuron protection function participates in pathological process of the diseases.


Assuntos
Transtorno Bipolar/genética , Esquizofrenia/genética , Adulto , Idoso , Estudos de Casos e Controles , Diferenciação Celular/genética , Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/fisiopatologia , Análise de Sequência com Séries de Oligonucleotídeos , Regulação para Cima/genética , Adulto Jovem
10.
Mol Psychiatry ; 18(3): 340-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22212596

RESUMO

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Cerebelo/metabolismo , Estudo de Associação Genômica Ampla , Humanos , Metilação , Polimorfismo de Nucleotídeo Único/genética
11.
Mol Psychiatry ; 17(8): 818-26, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21769101

RESUMO

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.


Assuntos
Transtorno Bipolar/genética , Ligação Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Transtornos Psicóticos/genética , Transtorno Bipolar/complicações , Transtorno Depressivo Maior/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/complicações
13.
Am J Med Genet B Neuropsychiatr Genet ; 153B(2): 549-553, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-19691043

RESUMO

The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female) = 1.79, P = 8.9 x 10(-5) vs. OR(Male) = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support.


Assuntos
Transtorno Bipolar/genética , Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Tecido Nervoso/genética , Serina Endopeptidases/genética , Alelos , Saúde da Família , Feminino , Marcadores Genéticos , Genótipo , Humanos , Masculino , Modelos Genéticos , Neurônios/metabolismo , Controle de Qualidade , Fatores de Risco , Esquizofrenia/genética , Fatores Sexuais
14.
Mol Psychiatry ; 14(8): 755-63, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19488044

RESUMO

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.


Assuntos
Afro-Americanos/genética , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Transtorno Bipolar/etnologia , Estudos de Casos e Controles , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Feminino , Genoma Humano , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valores de Referência , Adulto Jovem
15.
Mol Psychiatry ; 14(3): 261-8, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18180755

RESUMO

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.


Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Proteínas de Ligação a Tacrolimo/genética , Transtorno Bipolar/fisiopatologia , Estudos de Coortes , Haplótipos , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Desequilíbrio de Ligação , Transtornos do Humor/genética , Transtornos do Humor/fisiopatologia , Linhagem , Sistema Hipófise-Suprarrenal/fisiopatologia , Polimorfismo de Nucleotídeo Único
16.
Mol Psychiatry ; 14(4): 376-80, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19114987

RESUMO

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania

Assuntos
Transtorno Bipolar/genética , Predisposição Genética para Doença , Genoma Humano/genética , Deleção de Sequência/genética , Estudos de Casos e Controles , Feminino , Dosagem de Genes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Risco
19.
Mol Psychiatry ; 12(7): 630-9, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17505464

RESUMO

Despite compelling evidence that genetic factors contribute to bipolar disorder (BP), attempts to identify susceptibility genes have met with limited success. This may be due to the genetic heterogeneity of the disorder. We sought to identify susceptibility loci for BP in a genome-wide linkage scan with and without clinical covariates that might reflect the underlying heterogeneity of the disorder. We genotyped 428 subjects in 98 BP families at the Center for Inherited Disease Research with 402 microsatellite markers. We first carried out a non-parametric linkage analysis with MERLIN, and then reanalyzed the data with LODPAL to incorporate clinical covariates for age at onset (AAO), psychosis and comorbid anxiety. We sought to further examine the top findings in the covariate analysis in an independent sample of 64 previously collected BP families. In the non-parametric linkage analysis, three loci were nominally significant under a narrow diagnostic model and seven other loci were nominally significant under a broader model. The top findings were on chromosomes 2q24 and 3q28. The covariate analyses yielded additional evidence for linkage on 3q28 with AAO in the primary and independent samples. Although none of the linked loci were genome-wide significant, their congruence with prior results and, for the covariate analyses, their identification in two separate samples increases the likelihood that they are true positives and deserve further investigation. These findings further demonstrate the value of considering clinical features that may reflect the underlying heterogeneity of disease in order to facilitate gene mapping.


Assuntos
Transtorno Bipolar/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Ligação Genética , Predisposição Genética para Doença/genética , Idade de Início , Transtorno Bipolar/classificação , Mapeamento Cromossômico , Humanos , Transtornos do Humor/classificação , Transtornos do Humor/genética , Linhagem , Estatísticas não Paramétricas
20.
J Endocrinol ; 188(3): 531-48, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16522733

RESUMO

Ovulation-selective/specific genes, that is, genes preferentially or exclusively expressed during the ovulatory process, have been the subject of growing interest. We report herein studies on the use of suppression subtractive hybridization (SSH) to construct a 'forward' ovulation-selective/specific cDNA library. In toto, 485 clones were sequenced and analyzed for homology to known genes with the basic local alignment tool (BLAST). Of those, 252 were determined to be nonredundant. Of these 252 nonredundant clones, 98 were analyzed by probing mouse preovulatory and postovulatory ovarian cDNA. Twenty-five clones (26%) failed to show any signal, and 43 cDNAs tested thus far display a true ovulation-selective/specific expression pattern. In this communication, we focus on one such ovulation-selective gene, the fatty acid elongase 1 (FAE-1) homolog, found to be localized to the inner periantral granulosa and to the cumulus granulosa cells of antral follicles. The FAE-1 gene is a beta-ketoacyl-CoA synthase belonging to the fatty acid elongase (ELO) family, which catalyzes the initial step of very long-chain fatty acid synthesis. All in all, the present study accomplished systematic identification of those hormonally regulated genes that are expressed in the ovary in an ovulation-selective/specific manner. These ovulation-selective/specific genes may have significant implications for the understanding of ovarian function in molecular terms and for the development of innovative strategies for both the promotion of fertility and its control.


Assuntos
DNA Complementar/genética , Biblioteca Gênica , Ovulação/genética , Acetiltransferases/genética , Animais , Sequência de Bases , Northern Blotting/métodos , Clonagem Molecular , Inibidores de Ciclo-Oxigenase/farmacologia , Feminino , Regulação da Expressão Gênica , Células da Granulosa/metabolismo , Hibridização In Situ/métodos , Indometacina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
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