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首页> 外文学位 >Fine mapping of autism susceptibility loci on chromosome 1q23-q24 and chromosome 13q13-q14.
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Fine mapping of autism susceptibility loci on chromosome 1q23-q24 and chromosome 13q13-q14.

机译：在染色体1q23-q24和染色体13q13-q14上自闭症易感基因座的精细定位。

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摘要

Autism Spectrum Disorders (ASD) are complex neurodevelopmental disorders where genetic heterogeneity has complicated the identification of genes involved in the pathogenesis in these disorders. To address this issue, we fine mapped a 30cM linkage interval on chromosome 1q23-q24 through high density microsatellite genotyping of 46 phenotypically homogeneous families described by Bartlett et al. (2005) who re-analyzed the Autism Genetic Resource Exchange (AGRE) genome scan by the Posterior Probability of Linkage (PPL). We identified genotyping errors in the original AGRE genome scan that led to an inflation of the linkage signal (PPL of 0.55) due to a false assumption of identity-by-descent (IBD). Our Multipoint PPL analysis narrowed the 30cM linkage interval to 5cM (PPL of 0.27). Subsequently, the Posterior Probability of Linkage Disequilibrium (PPLD) analysis of the AGRE 550K SNP data generated by the Autism Genome Project Consortium (AGP) and 116 tag SNPs genotyped and analyzed in our lab for the pre-B-cell leukemia transcription factor 1 (PBX1), provided the highest PPLD score for rs2800785 (0.13 and 0.12 respectively) which indicates possible association for rs2800785 (located in intron 2 of PBX1) with the trait locus. In addition, PDTPHASE single and multilocus analysis for the 116 tagSNPs showed association for rs7529254 which remained statistically significant (nominal P-value=0.0006) after correction for multiple testing with the simple M method by Gao, (alphacorrected=0.05/58)=0.0009. Four-marker PDTPHASE haplotype analysis showed transmission disequilibrium for rs1780334, rs7529254, rs2792253 and rs2800785. Global Chi-squared tests for all haplotypes produced a nominal P-value of 0.0077.;The second locus investigated was identified by multipoint PPL genome scan analysis of the 10K SNP data generated by the AGP. Ninety nine phenotypically homogeneous families were used to identify a 1.5 Mb linkage peak on chromosome 13q13-q14 with a maximum multipoint PPL score of 0.38. PPLD analysis of 142 genotyped tagSNPs from a 620.5kb peak interval which included TSC22D1, NUFIP1 and KIAA1704 showed weak evidence of LD.;No other studies have proposed PBX1 as a candidate gene for ASD. However, our positive association results with the two-point PPLD and single and multimarker PDTPHASE analysis suggests PBX1 as a likely susceptibility gene for ASD that warrants further investigation.
机译：自闭症谱系障碍（ASD）是复杂的神经发育障碍，遗传异质性使这些疾病的发病机理中涉及的基因的鉴定变得复杂。为了解决这个问题，我们通过Bartlett等人描述的46个表型同质科的高密度微卫星基因分型，在1q23-q24染色体上精确绘制了30cM的连锁间隔。 （2005年），他们通过连锁的后验概率（PPL）重新分析了自闭症遗传资源交换（AGRE）基因组扫描。我们在原始AGRE基因组扫描中发现了基因分型错误，由于错误假设了后裔身份（IBD），导致连锁信号膨胀（PPL为0.55）。我们的多点PPL分析将3​​0cM链接间隔缩小到5cM（PPL为0.27）。随后，对自闭症基因组计划联盟（AGP）和116个标签SNP产生的AGRE 550K SNP数据进行连锁不平衡的后验概率分析（PPLD），在我们的实验室中对B细胞前白血病转录因子1进行了基因分型和分析（ PBX1）为rs2800785提供了最高的PPLD评分（分别为0.13和0.12），表明rs2800785（位于PBX1的内含子2中）与性状基因座的可能关联。此外，对116种tagSNP的PDTPHASE单基因座和多基因座分析显示，与rs7529254关联，在用Gao用简单M方法校正多次测试后校正后，rs7529254仍然具有统计学显着性（名义P值= 0.0006）（alpha校正= 0.05 / 58）= 0.0009 。四标记PDTPHASE单倍型分析显示rs1780334，rs7529254，rs2792253和rs2800785的传输不平衡。所有单倍型的全球卡方检验得出的名义P值为0.0077 .;通过对AGP生成的10K SNP数据进行多点PPL基因组扫描分析，确定了调查的第二个基因座。使用九十九个表型上同质的家族来鉴定染色体13q13-q14上的1.5 Mb连锁峰，最大多点PPL得分为0.38。从620.5kb峰间隔（包括TSC22D1，NUFIP1和KIAA1704）对142个基因型标签SNP的PPLD分析显示，LD的证据微弱。;尚无其他研究提出将PBX1作为ASD候选基因。但是，我们与两点PPLD以及单标记和多标记PDTPHASE分析的正相关结果表明，PBX1是ASD的易感基因，值得进一步研究。

著录项

  • 作者

    Garavito, Maria del Pilar.;

  • 作者单位

    Rutgers The State University of New Jersey - New Brunswick.;

  • 授予单位 Rutgers The State University of New Jersey - New Brunswick.;
  • 学科 Biology Neuroscience.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 218 p.
  • 总页数 218
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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