RESUMO
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single dominant hematopoietic stem cell lineage. Somatic mutations in candidate driver (CD) genes are thought to be responsible for at least some cases of CH. Using whole-genome sequencing of 11 262 Icelanders, we found 1403 cases of CH by using barcodes of mosaic somatic mutations in peripheral blood, whether or not they have a mutation in a CD gene. We find that CH is very common in the elderly, trending toward inevitability. We show that somatic mutations in TET2, DNMT3A, ASXL1, and PPM1D are associated with CH at high significance. However, known CD mutations were evident in only a fraction of CH cases. Nevertheless, the highly prevalent CH we detect associates with increased mortality rates, risk for hematological malignancy, smoking behavior, telomere length, Y-chromosome loss, and other phenotypic characteristics. Modeling suggests some CH cases could arise in the absence of CD mutations as a result of neutral drift acting on a small population of active hematopoietic stem cells. Finally, we find a germline deletion in intron 3 of the telomerase reverse transcriptase (TERT) gene that predisposes to CH (rs34002450; P = 7.4 × 10-12; odds ratio, 1.37).
Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Hematopoese , Células-Tronco Hematopoéticas/citologia , Mutação , Proteína Fosfatase 2C/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Células Clonais , DNA Metiltransferase 3A , Dioxigenases , Feminino , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The ages of puberty, first sexual intercourse and first birth signify the onset of reproductive ability, behavior and success, respectively. In a genome-wide association study of 125,667 UK Biobank participants, we identify 38 loci associated (P < 5 × 10(-8)) with age at first sexual intercourse. These findings were taken forward in 241,910 men and women from Iceland and 20,187 women from the Women's Genome Health Study. Several of the identified loci also exhibit associations (P < 5 × 10(-8)) with other reproductive and behavioral traits, including age at first birth (variants in or near ESR1 and RBM6-SEMA3F), number of children (CADM2 and ESR1), irritable temperament (MSRA) and risk-taking propensity (CADM2). Mendelian randomization analyses infer causal influences of earlier puberty timing on earlier first sexual intercourse, earlier first birth and lower educational attainment. In turn, likely causal consequences of earlier first sexual intercourse include reproductive, educational, psychiatric and cardiometabolic outcomes.
Assuntos
Fatores Etários , Comportamento , Coito , Comportamento Sexual , Adolescente , Adulto , Moléculas de Adesão Celular/genética , Receptor alfa de Estrogênio/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas de Membrana/genética , Metionina Sulfóxido Redutases/genética , Proteínas do Tecido Nervoso/genética , Puberdade , Proteínas de Ligação a RNA/genética , Adulto JovemRESUMO
Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).
Assuntos
Neoplasias da Mama/genética , Carcinoma Basocelular/genética , Caspase 8/genética , Neoplasias da Próstata/genética , Splicing de RNA , Retroelementos , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Bases , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patologia , Caspase 8/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/prevenção & controle , Fatores de Proteção , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
In an ongoing screen for DNA sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conduct a genome-wide association study (GWAS) of 24,988,228 SNPs and small indels detected through whole-genome sequencing of 2,636 Icelanders and imputed into 4,572 BCC patients and 266,358 controls. Here we show the discovery of four new BCC susceptibility loci: 2p24 MYCN (rs57244888[C], OR=0.76, P=4.7 × 10(-12)), 2q33 CASP8-ALS2CR12 (rs13014235[C], OR=1.15, P=1.5 × 10(-9)), 8q21 ZFHX4 (rs28727938[G], OR=0.70, P=3.5 × 10(-12)) and 10p14 GATA3 (rs73635312[A], OR=0.74, P=2.4 × 10(-16)). Fine mapping reveals that two variants correlated with rs73635312[A] occur in conserved binding sites for the GATA3 transcription factor. In addition, expression microarrays and RNA-seq show that rs13014235[C] and a related SNP rs700635[C] are associated with expression of CASP8 splice variants in which sequences from intron 8 are retained.
Assuntos
Carcinoma Basocelular/genética , Caspase 8/genética , Fator de Transcrição GATA3/genética , Proteínas de Homeodomínio/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Proteínas/genética , Neoplasias Cutâneas/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Islândia , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Proteína Proto-Oncogênica N-Myc , População Branca/genética , Adulto JovemRESUMO
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.
Assuntos
Antígenos de Superfície/genética , Carcinoma Basocelular/genética , Reguladores de Proteínas de Ligação ao GTP/genética , Variação Genética , Mutação em Linhagem Germinativa , Transglutaminases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Células Germinativas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/genética , Adulto JovemRESUMO
Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.
Assuntos
Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Idoso , Carcinoma de Células Renais/epidemiologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Genótipo , Humanos , Islândia/epidemiologia , Neoplasias Renais/epidemiologia , Razão de Chances , Fatores de RiscoRESUMO
Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.
Assuntos
Deficiência de Ácido Fólico/genética , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas , Vitamina B 12/sangue , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Dinamarca , Exoma , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/metabolismo , Genoma Humano , Humanos , Islândia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Vitamina B 12/metabolismoRESUMO
Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.
Assuntos
Neoplasias do Sistema Biliar/genética , Densidade Óssea/genética , Carcinoma de Células Escamosas/genética , Códon sem Sentido/genética , Fraturas por Osteoporose/genética , Receptores Acoplados a Proteínas G/genética , Neoplasias Cutâneas/genética , Desequilíbrio Hidroeletrolítico/genética , Animais , Austrália , Dinamarca , Regulação para Baixo/genética , Feminino , Heterozigoto , Humanos , Islândia , Masculino , Menarca/genética , Camundongos , Camundongos Knockout , Fenótipo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/metabolismo , Testosterona/análiseRESUMO
In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.
Assuntos
Adenocarcinoma/genética , Mutação , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Linhagem Celular , Cromossomos Humanos Par 8 , Frequência do Gene , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/genética , Humanos , Islândia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Risco , Análise de Sequência de DNA , População Branca/genéticaRESUMO
To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10(-8) in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; P(combined) = 1.3 × 10(-9)), rs2439302 on 8p12 (OR = 1.36; P(combined) = 2.0 × 10(-9)) and rs116909374 on 14q13.3 (OR = 2.09; P(combined) = 4.6 × 10(-11)), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10(-91)) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.
Assuntos
Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Neoplasias da Glândula Tireoide/genética , Tireotropina/metabolismo , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Islândia , Neuregulina-1/sangue , Neuregulina-1/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.
Assuntos
Proteínas de Ligação a DNA/genética , Mutação , Neoplasias Ovarianas/genética , RNA Helicases/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.
Assuntos
Cromossomos Humanos Par 15 , Neoplasias Pulmonares/genética , Polimorfismo Genético , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Cromossomos Humanos Par 15/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Islândia/epidemiologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Pulmonares/epidemiologia , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Polimorfismo Genético/fisiologia , Fatores de Risco , Espanha/epidemiologia , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.
Assuntos
Biomarcadores Tumorais/genética , Detecção Precoce de Câncer/métodos , Marcadores Genéticos/genética , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico , Biomarcadores Tumorais/sangue , Humanos , Calicreínas/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Proteínas Secretadas pela Próstata/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Proteínas com Domínio T/genética , Telomerase/genéticaRESUMO
Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five-one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes-have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.
Assuntos
Pai , Predisposição Genética para Doença/genética , Mães , Polimorfismo de Nucleotídeo Único/genética , Alelos , Sítios de Ligação , Neoplasias da Mama/genética , Fator de Ligação a CCCTC , Carcinoma Basocelular/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 7/genética , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Genoma Humano/genética , Impressão Genômica/genética , Haplótipos , Humanos , Islândia , Masculino , Linhagem , Proteínas Repressoras/metabolismoRESUMO
We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 x 10(-15)) and rs445114[T] (OR = 1.14, P = 4.7 x 10(-10)), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 x 10(-11)) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.
Assuntos
Replicação do DNA , DNA/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Suscetibilidade a Doenças , Humanos , Islândia , Masculino , Neoplasias da Próstata/epidemiologia , Fatores de Risco , População Branca/genéticaRESUMO
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 x 10(-27)) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 x 10(-9)). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T(4)) and high concentration of triiodothyronine (T(3)).
Assuntos
Cromossomos Humanos Par 4 , Cromossomos Humanos Par 9 , Predisposição Genética para Doença/genética , Variação Genética , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Europa (Continente)/epidemiologia , Fatores de Transcrição Forkhead/genética , Humanos , Tireotropina/sangue , Tiroxina/sangue , Fatores de Transcrição , Tri-Iodotironina/sangueRESUMO
To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 x 10(-12)) and rs801114 on 1q42 (OR = 1.28, P = 5.9 x 10(-12)). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.
Assuntos
Carcinoma Basocelular/genética , Cromossomos Humanos Par 1/genética , Predisposição Genética para Doença , Melanoma/genética , Mutação/genética , Pigmentação/genética , Neoplasias Cutâneas/genética , Tecido Adiposo/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Alelos , Carcinoma Basocelular/diagnóstico , Carcinoma de Células Escamosas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , RNA/metabolismo , Neoplasias Cutâneas/diagnósticoRESUMO
Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 x 10(-9)) and BCC (OR = 1.33, P = 1.2 x 10(-6)). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 x 10(-7)) and BCC (OR = 1.14, P = 6.1 x 10(-4)). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 x 10(-4)). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.
Assuntos
Proteína Agouti Sinalizadora/genética , Carcinoma Basocelular/genética , Melanoma/genética , Monofenol Mono-Oxigenase/genética , Pigmentação/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/patologia , Estudos de Casos e Controles , Europa (Continente) , Cor de Olho/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Melanoma/patologia , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Metástase Neoplásica , Razão de Chances , Oxirredutases/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Sistema de Registros , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture. METHODS: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively). RESULTS: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2x10(-7) to 2.0x10(-21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-kappaB ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappaB gene (RANK), and loci at 2p16 and 11p11. CONCLUSIONS: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis.
Assuntos
Densidade Óssea/genética , Receptor alfa de Estrogênio/genética , Fraturas Ósseas/genética , Osteoporose/genética , Osteoprotegerina/genética , Ligante RANK/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Dinamarca , Feminino , Genótipo , Humanos , Islândia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características QuantitativasRESUMO
The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.