Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder.
Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder.
复制标题
DOI：
10.1186/2040-2392-5-13
复制
发表时间：
2014-02-17
期刊：
影响因子：
6.2
通讯作者：
Geschwind DH
中科院分区：
文献类型：
--
作者：
Werling DM;Lowe JK;Luo R;Cantor RM;Geschwind DH
自闭症谱系障碍(ASD)是男性偏见和遗传异质性的。虽然对零星病例的测序已经确定了从头开始的风险变异，但对可遗传的遗传贡献和驱动男性偏见的机制了解较少。在这里，我们的目标是在自闭症遗传资源交易所(AGRE)提供的最大可用、统一确定的、密集基因分型的多重ASD家系样本中识别家族性和性别差异的风险基因，并将结果与AGRE的早期发现进行比较。从1008个多基因家庭的总样本中，我们对发现样本中的847个家庭进行了全基因组非参数连锁分析，并分别对只有男性、受影响儿童(男性，MO)或至少有一个女性、受影响儿童(FC)的家庭子集进行了分析。在一项利用所有1,008个可用家系的扩展研究中，对本次发现样本或以前的≥样本中显示暗示连锁的证据(优势对数AGRE 2.2)的基因座进行了重新评估。对于发现阶段具有全基因组显著连锁信号的区域，然后评估那些未包括在相应发现样本中的家系是否独立复制连锁。常见的单核苷酸多态(SNPs)的关联检验也在暗示连锁区域进行。我们观察到染色体20p13(P <； 0.01)上的连锁独立复制，而6q27和8q13.2上的座位在我们的扩大样本中显示出暗示的连锁。在我们发现的样本中，在1p31.3(MO)、8p21.2(FC)和8p12(FC)处观察到提示性差异连锁，并且在我们的扩展样本中支持1p31.3处的MO信号。没有性别差异信号符合复制标准，在任何已识别的连锁区域中，也没有共同的SNP与ASD显著相关。除极少数例外，对AGRE队列中的家系子集的分析确定了不同的风险基因，这与ASD中极端的基因座异质性一致。大样本似乎产生了更一致的结果，性别分层分析有助于识别性别差异的风险基因座，这表明在大队列中的连锁分析对于识别可遗传的风险基因座是有用的。需要额外的工作，如有针对性的重新测序，以确定这些基因座中导致ASD风险增加的特定变异。
Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE. From a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds ≥2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions. We observed an independent replication of previously observed linkage at chromosome 20p13 (P < 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions. With few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk.
登录
查看更多内容
影响因子：
16.2
作者：
Iossifov I;Ronemus M;Levy D;Wang Z;Hakker I;Rosenbaum J;Yamrom B;Lee YH;Narzisi G;Leotta A;Kendall J;Grabowska E;Ma B;Marks S;Rodgers L;Stepansky A;Troge J;Andrews P;Bekritsky M;Pradhan K;Ghiban E;Kramer M;Parla J;Demeter R;Fulton LL;Fulton RS;Magrini VJ;Ye K;Darnell JC;Darnell RB;Mardis ER;Wilson RK;Schatz MC;McCombie WR;Wigler M
通讯作者：
Wigler M
DOI：
10.1176/appi.ajp.2010.09101470
发表时间：
2010-11
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Constantino JN;Zhang Y;Frazier T;Abbacchi AM;Law P
通讯作者：
Law P
影响因子：
10.6
作者：
Constantino, JN;Todd, RD
通讯作者：
Todd, RD
影响因子：
4.8
作者：
Dai, YM;Yang, Y;Sanderson, RD
通讯作者：
Sanderson, RD
影响因子：
6.9
作者：
BAILEY, A;LECOUTEUR, A;RUTTER, M
通讯作者：
RUTTER, M