Department of Pathology, Laboratory Medicine, Biomedical Graduate Studies, University of Pennsylvania, Philadelphia 19104, USA.
BMC Med Genet. 2010 Sep 21;11:134. doi: 10.1186/1471-2350-11-134.
Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis.
As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations.
Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 × 10(-3)). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019).
Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation.
全基因组研究自闭症谱系障碍（ASD）主要集中在大规模的人群样本，但对隔离人群中的罕见变异的检测可能为疾病发病机制提供更多的见解。
作为在克罗地亚对 ASD 进行遗传分析的第一步，我们对 103 名 ASD 患者和 203 名对照个体的样本进行了遗传变异特征分析，这些个体使用 Illumina HumanHap550 BeadChip 进行了基因分型。我们分析了克罗地亚人群的遗传多样性及其与其他人群的关系、通过 Runs of Homozygosity（ROHs）的亲缘关系程度以及大（>500 Kb）拷贝数变异的分布。
将克罗地亚队列与 FastME 分析（替代邻接法的一种）中以前发表的几个队列合并，结果表明，如预期的那样，克罗地亚个体与南欧人聚类；此外，来自欧洲同一地理区域的个体也聚类在一起。虽然克罗地亚个体可以与来自北美的欧洲裔健康对照个体区分开来，但克罗地亚的 ASD 病例和对照个体混合在一起。对 Runs of Homozygosity 的比较表明，与对照组相比，ASD 患者的同型合子区域的数量和中位数长度更高（p = 6×10(-3)）。此外，拷贝数变异分析发现，ASD 病例中（5/103）大染色体重排（>2 Mb）的频率高于对照组（1/197，p = 0.019）。
我们的发现说明了高密度基因型数据对于来自有限地理区域的个体在解析与人群和疾病相关的遗传异质性方面的巨大应用价值。
