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1.
J Dent Res ; 97(5): 515-522, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29364747

RESUMO

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.


Assuntos
Anodontia/genética , Anodontia/epidemiologia , Anodontia/etiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Islândia/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
2.
J Phys Condens Matter ; 28(43): 433003, 2016 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-27602484

RESUMO

This review presents MAX phases (M is a transition metal, A an A-group element, X is C or N), known for their unique combination of ceramic/metallic properties, as a recently uncovered family of novel magnetic nanolaminates. The first created magnetic MAX phases were predicted through evaluation of phase stability using density functional theory, and subsequently synthesized as heteroepitaxial thin films. All magnetic MAX phases reported to date, in bulk or thin film form, are based on Cr and/or Mn, and they include (Cr,Mn)2AlC, (Cr,Mn)2GeC, (Cr,Mn)2GaC, (Mo,Mn)2GaC, (V,Mn)3GaC2, Cr2AlC, Cr2GeC and Mn2GaC. A variety of magnetic properties have been found, such as ferromagnetic response well above room temperature and structural changes linked to magnetic anisotropy. In this paper, theoretical as well as experimental work performed on these materials to date is critically reviewed, in terms of methods used, results acquired, and conclusions drawn. Open questions concerning magnetic characteristics are discussed, and an outlook focused on new materials, superstructures, property tailoring and further synthesis and characterization is presented.

3.
Transl Psychiatry ; 5: e656, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26460480

RESUMO

Antagonists of the N-methyl-D-aspartate (NMDA)-type glutamate receptor induce psychosis in healthy individuals and exacerbate schizophrenia symptoms in patients. In this study we have produced an animal model of NMDA receptor hypofunction by chronically treating rats with low doses of the NMDA receptor antagonist MK-801. Subsequently, we performed an expression study and identified 20 genes showing altered expression in the brain of these rats compared with untreated animals. We then explored whether the human orthologs of these genes are associated with schizophrenia in the largest schizophrenia genome-wide association study published to date, and found evidence for association for 4 out of the 20 genes: SF3B1, FOXP1, DLG2 and VGLL4. Interestingly, three of these genes, FOXP1, SF3B1 and DLG2, have previously been implicated in neurodevelopmental disorders.


Assuntos
Maleato de Dizocilpina/farmacologia , Fatores de Transcrição Forkhead/genética , Guanilato Quinases/genética , Hipocampo , Fosfoproteínas/genética , Proteínas Repressoras/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Esquizofrenia , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Animais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Psicotrópicos/farmacologia , Fatores de Processamento de RNA , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Esquizofrenia/genética , Esquizofrenia/patologia
4.
Mol Psychiatry ; 19(1): 108-14, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23164818

RESUMO

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).


Assuntos
Transtorno Bipolar/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 16/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Europa (Continente) , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Razão de Chances , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Risco , Esquizofrenia/complicações , Esquizofrenia/epidemiologia , Adulto Jovem
5.
Phys Rev Lett ; 110(19): 195502, 2013 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-23705717

RESUMO

The first experimental realization of a magnetic M(n+1)AX(n) (MAX) phase, (Cr(0.75)Mn(0.25))(2)GeC, is presented, synthesized as a heteroepitaxial single crystal thin film, exhibiting excellent structural quality. This self-organized atomic laminate is based on the well-known Cr(2)GeC, with Mn, a new element in MAX phase research, substituting Cr. The compound was predicted using first-principles calculations, from which a variety of magnetic behavior is envisaged, depending on the Mn concentration and Cr/Mn atomic configuration within the sublattice. The analyzed thin films display a magnetic signal at room temperature.

6.
Transl Psychiatry ; 3: e326, 2013 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-26151896

RESUMO

Schizophrenia (SCZ) is a severe and debilitating neuropsychiatric disorder with an estimated heritability of ~80%. Recently, de novo mutations, identified by next-generation sequencing (NGS) technology, have been suggested to contribute to the risk of developing SCZ. Although these studies show an overall excess of de novo mutations among patients compared with controls, it is not easy to pinpoint specific genes hit by de novo mutations as actually involved in the disease process. Importantly, support for a specific gene can be provided by the identification of additional alterations in several independent patients. We took advantage of existing genome-wide single-nucleotide polymorphism data sets to screen for deletions or duplications (copy number variations, CNVs) in genes previously implicated by NGS studies. Our approach was based on the observation that CNVs constitute part of the mutational spectrum in many human disease-associated genes. In a discovery step, we investigated whether CNVs in 55 candidate genes, suggested from NGS studies, were more frequent among 1637 patients compared with 1627 controls. Duplications in RB1CC1 were overrepresented among patients. This finding was followed-up in large, independent European sample sets. In the combined analysis, totaling 8461 patients and 112 871 controls, duplications in RB1CC1 were found to be associated with SCZ (P=1.29 × 10(-5); odds ratio=8.58). Our study provides evidence for rare duplications in RB1CC1 as a risk factor for SCZ.


Assuntos
Duplicação Gênica/genética , Predisposição Genética para Doença/genética , Proteínas Tirosina Quinases/genética , Esquizofrenia/genética , Adulto , Idoso , Proteínas Relacionadas à Autofagia , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Mol Psychiatry ; 16(1): 17-25, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19786961

RESUMO

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 16 , Variações do Número de Cópias de DNA , Esquizofrenia/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Mapeamento Cromossômico , Feminino , Humanos , Masculino , Valores de Referência , Duplicações Segmentares Genômicas/genética , Deleção de Sequência/genética , Adulto Jovem
8.
Mol Psychiatry ; 16(1): 59-66, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20048749

RESUMO

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).


Assuntos
Transtornos de Ansiedade/genética , Transtorno Bipolar/genética , Variações do Número de Cópias de DNA/genética , Fatores de Transcrição Kruppel-Like/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Valores de Referência
9.
Mol Psychiatry ; 16(11): 1117-29, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20838396

RESUMO

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values ≤0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 × 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 × 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted.


Assuntos
Estudo de Associação Genômica Ampla , Proteínas Musculares/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Negro ou Afro-Americano/genética , Proteínas de Transporte/genética , Estudos de Casos e Controles , Mineração de Dados , Disbindina , Proteínas Associadas à Distrofina , Alemanha/epidemiologia , Alemanha/etnologia , Humanos , Irlanda/epidemiologia , Judeus/genética , Desequilíbrio de Ligação , Pennsylvania/epidemiologia , Risco , Esquizofrenia/epidemiologia , Esquizofrenia/etnologia , População Branca/genética
10.
Rev Sci Instrum ; 78(10): 103901, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17979429

RESUMO

We describe a versatile three gun magnetron sputtering system with a custom made sample holder for in situ electrical resistance measurements, both during film growth and ambient changes on film electrical properties. The sample holder allows for the preparation of patterned thin film structures, using up to five different shadow masks without breaking vacuum. We show how the system is used to monitor the electrical resistance of thin metallic films during growth and to study the thermodynamics of hydrogen uptake in metallic thin films. Furthermore, we demonstrate the growth of thin film capacitors, where patterned films are created using shadow masks.


Assuntos
Eletroquímica/instrumentação , Magnetismo/instrumentação , Teste de Materiais/instrumentação , Membranas Artificiais , Impedância Elétrica , Eletroquímica/métodos , Desenho de Equipamento , Análise de Falha de Equipamento , Teste de Materiais/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
11.
Mol Psychiatry ; 9(7): 698-704, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15007393

RESUMO

To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5' end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP(China 1)), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP(China 2)) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3' end of the NRG1 gene, HAP(China 3), was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese.


Assuntos
Povo Asiático/genética , Neuregulina-1/genética , Esquizofrenia/etnologia , Esquizofrenia/genética , Estudos de Casos e Controles , China/epidemiologia , Marcadores Genéticos , Predisposição Genética para Doença/etnologia , Haplótipos , Humanos , Islândia/epidemiologia , Fatores de Risco , Escócia/epidemiologia , População Branca/genética
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