Genetic Factors in Birth Defects

出生缺陷的遗传因素

• 批准号: 8736884
• 负责人: James Mills
• 金额: $ 67.3万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736884
• 关键词: Affect; Animals; Apical Ectodermal Ridge; BMP2 gene; BMP4; Binding; Binding Sites; Birth; Blood; CTNNB1 gene; CYP26B1 gene; Candidate Disease Gene; Case-Control Studies; Child; Coagulation Process; Collaborations; Confidence Intervals; Congenital Abnormality; Craniosynostosis; DNA; DNA Methylation; Data; Defect; Diet; Etiology; European; FGF10 gene; FGF8 gene; Folate; Future; GDF5 gene; GLI2 gene; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Genotype; HIF1A gene; Health; Heterogeneity; Human; Individual; Infant; Institution; Investigation; Lead; Limb Development; Limb structure; Link; Literature; Meta-Analysis; Methylenetetrahydrofolate reductase (NADPH); MicroRNAs; Minor; Mothers; NOS3 gene; Neonatal Screening; New York; Newborn Infant; Not Hispanic or Latino; Obesity; Odds Ratio; Paper; Parents; Plasma; Play; Population; Population Study; Pregnancy; Publication Bias; Publishing; RNA Splicing; Race; Registries; Reporting; Research; Research Personnel; Resources; Risk; Risk Factors; Role; SHH gene; Sampling; Single Nucleotide Polymorphism; Site; Skeletal Development; Spearman Rank Correlation Coefficient; Subgroup; Syndrome; TCF7L2 gene; Testing; VEGFA gene; Variant; WNT7A gene; angiogenesis; base; case control; congenital heart disorder; design; expectation; genetic association; genetic risk factor; genetic variant; genome wide association study; heart disease risk; interest; malformation; offspring; population based; proband; programs; retinoic acid 4-hydroxylase; transcription factor

DNA has been obtained from approximately 20 major malformations for current and future investigations. We have recently expanded our investigations to include searching for copy number variants in rare defects. New York has an exceptionally valuable research resource in having approximately 250,000 births per year from which to identify children with rare defects. In addition to classic candidate gene approaches, cases have been selected for copy number variant studies. Samples have been analyzed by large scale copy number variant array testing. The first defects are now being analyzed for copy number variants. We have also collaborated with large groups doing genome wide association studies. Samples have been tested in cases and controls in collaboration providing subjects for confirmatory genotyping in several studies. Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio OR, 0.96 95% confidence interval, 0.87-1.07). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 95% confidence interval, 1.03-1.51; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 95% confidence interval, 0.91-1.03) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 95% confidence interval, 0.87-1.47). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association. Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 10(-10), OR = 0.19) and rs17724206 (P = 1.50 10(-8), OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 10(-31) and rs10262453, P = 3.50 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC. Anorectal atresia is a serious birth defect of largely unknown etiology but candidate genes have been identified in animal studies and human syndromes. Because alterations in the activity of these genes might lead to anorectal atresia, we selected 71 common variants predicted to be in transcription factor binding sites, CpG windows, splice sites, and miRNA target sites of 25 candidate genes, and tested for their association with anorectal atresia. The study population comprised 150 anorectal atresia cases and 623 control infants without major malformations. Variants predicted to affect transcription factor binding, splicing, and DNA methylation in WNT3A, PCSK5, TCF4, MKKS, GLI2, HOXD12, and BMP4 were associated with anorectal atresia based on a nominal P value < 0.05. The GLI2 and BMP4 variants are reported to be moderately associated with gene expression changes (Spearman's rank correlation coefficients between -0.260 and 0.226). We did not find evidence for interaction between maternal pre-pregnancy obesity and variants in MKKS, a gene previously associated with obesity, on the risk of anorectal atresia. Our results for MKKS support previously suggested associations with anorectal malformations. Our findings suggest that more research is needed to determine whether altered GLI2 and BMP4 expression is important in anorectal atresia in humans. We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LDs). Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998-2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR = 1.99; 95% CI = 1.43-2.77; uncorrected P = 0.000043 for rs10805683 heterozygous genotype, and OR = 2.37; 95% CI = 1.48-3.78; uncorrected P = 0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies.

已从大约 20 种主要畸形中获取 DNA，用于当前和未来的研究。 我们最近扩大了调查范围，包括搜索罕见缺陷中的拷贝数变异。 纽约拥有极其宝贵的研究资源，每年约有 250,000 名新生儿可以从中识别出患有罕见缺陷的儿童。除了经典的候选基因方法外，还选择病例进行拷贝数变异研究。样品已通过大规模拷贝数变异阵列测试进行了分析。 目前正在分析第一批缺陷的拷贝数变异。 我们还与大型团体合作进行全基因组关联研究。 样本已在病例和对照中进行了合作测试，为多项研究中的验证性基因分型提供了受试者。 亚甲基四氢叶酸还原酶 (MTHFR) 基因的 C677T 多态性与先天性心脏病 (CHD) 之间的关联存在争议。我们比较了 CHD 病例和对照之间以及 CHD 病例和对照的母亲之间的基因型。我们通过对之前发表的研究进行荟萃分析，将我们的结果置于背景中。在具有主要基因型数据的 5814 例病例和 10056 例对照中，没有证据表明 MTHFR C677T 基因型与 CHD 风险之间存在关联（比值比 OR，0.96 95% 置信区间，0.87-1.07）。对所有研究（涉及 7697 例病例和 13 125 例对照）的随机效应荟萃分析表明存在关联（OR，1.25 95% 置信区间，1.03-1.51；P=0.022），但贡献研究之间存在显着异质性（I (2)=64.4%）和发表偏倚的证据。仅对大型研究进行荟萃分析（由对数 OR <0.05 的方差定义），这些研究合计占所有病例的 83%，未得出任何关联证据（OR，0.97 95% 置信区间，0.91-1.03），无显着异质性(I(2)=0)。此外，对 1781 名 CHD 病例母亲（其中 829 名在本研究中进行了基因分型）和 19 861 名对照者的荟萃分析显示，没有证据表明母亲 C677T 基因型与后代 CHD 风险之间存在关联（OR，1.13 95% 置信区间，0.87 -1.47）。在来自不同膳食叶酸水平的地区的大型研究中，MTHFR 基因型与 CHD 风险之间没有显着关联。 MTHFR C677T 多态性直接影响血浆叶酸水平，与冠心病风险无关。发表偏倚似乎严重污染了有关这种遗传关联的文献。 矢状颅缝早闭是最常见的颅缝早闭形式，影响大约五千分之一的新生儿。据我们所知，我们使用 130 名欧洲血统的非西班牙裔病例父母三人组 (NHW) 进行了第一项非综合征矢状颅缝早闭 (sNSC) 的全基因组关联研究。我们在 BMP2 下游的 120 kb 区域中发现了强大的关联，该区域两侧是 rs1884302（P = 1.13 10(-14)，比值比 (OR) = 4.58）和 rs6140226（P = 3.40 10(-11)，OR = 0.24）且在 BBS9 的 167 kb 区域内rs10262453（P = 1.61 10（-10），OR = 0.19）和rs17724206（P = 1.50 10（-8），OR = 0.22）。我们在由 172 名具有 sNSC 的无关先证者和 548 名对照组成的独立 NHW 人群中复制了这两个基因座（rs1884302，P = 4.39 10(-31) 和 rs10262453，P = 3.50 10(-14)）的关联。 BMP2 和 BBS9 都是在骨骼发育中发挥作用的基因，需要进行功能研究以进一步了解 sNSC 的病因。 肛门直肠闭锁是一种严重的先天缺陷，其病因很大程度上未知，但已在动物研究和人类综合征中鉴定出候选基因。由于这些基因活性的改变可能导致肛门直肠闭锁，我们选择了 25 个候选基因的转录因子结合位点、CpG 窗口、剪接位点和 miRNA 靶位点中预测的 71 个常见变异，并测试了它们与肛门直肠闭锁的关联。闭锁。研究人群包括 150 名肛门直肠闭锁病例和 623 名没有严重畸形的对照婴儿。根据名义 P 值 < 0.05，预测影响 WNT3A、PCSK5、TCF4、MKKS、GLI2、HOXD12 和 BMP4 中转录因子结合、剪接和 DNA 甲基化的变异与肛门直肠闭锁相关。据报道，GLI2 和 BMP4 变体与基因表达变化中度相关（Spearman 等级相关系数在 -0.260 和 0.226 之间）。我们没有发现母亲孕前肥胖与 MKKS（一种先前与肥胖相关的基因）变异与肛门直肠闭锁风险之间存在相互作用的证据。我们的 MKKS 结果支持之前提出的与肛门直肠畸形的关联。我们的研究结果表明，需要更多的研究来确定 GLI2 和 BMP4 表达的改变对于人类肛门直肠闭锁是否重要。 我们对选定基因中的单核苷酸多态性 (SNP) 进行了一项基于人群的病例对照研究，以寻找在肢体缺陷 (LD) 病因学中发挥作用的常见变异。该研究包括 389 名不明原因 LD 的婴儿和 980 名未受影响的对照，这些对照选自 1998-2005 年纽约州 (NYS) 的所有出生婴儿。我们使用了纽约州卫生部 (DOH) 先天性畸形登记处确定的病例。获得了参与肢体发育（SHH、WNT7A、FGF4、FGF8、FGF10、TBX3、TBX5、SALL4、GREM1、GDF5、CTNNB1、EN1、CYP26A1、CYP26B1）、血管生成（VEGFA、HIF1A、NOS3）的基因中的 132 个 SNP 的基因型。和凝固（F2、F5、亚甲基四氢呋喃）。基因型检出率 >97%，并且按种族/族裔亚组测试了 SNP 是否偏离 Hardy-Weinberg 预期。对于每个 SNP，对所有 LD 组合和 LD 亚型的多重比较估计和校正优势比 (OR) 和置信区间 (CI)。在非西班牙裔白人婴儿中，FGF10 SNP rs10805683 和 rs13170645 与所有 LD 组合之间的关联在多重测试校正后具有统计学显着性（OR = 1.99；95% CI = 1.43-2.77；rs10805683 杂合基因型的未校正 P = 0.000043，并且 OR = 2.37；95% CI = 1.48-3.78；对于 rs13170645 纯合次要基因型，未校正 P = 0.00032）。我们还观察到与其他基因（包括 CYP26B1 和 WNT7A）中的 SNP 相关的提示性证据。动物研究表明，FGF10 可诱导顶端外胚层脊的形成，并且是肢体发育所必需的。我们的数据表明，FGF10 的常见变异会增加多种非综合征性肢体缺陷的风险。