Wang Liyong, Beecham Ashley, Dueker Nicole, Blanton Susan H, Rundek Tatjana, Sacco Ralph L
John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, 1120 NW 14th Street, Miami, FL, 33136, USA.
John T. Macdonald Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
Hum Genet. 2015 Oct;134(10):1127-38. doi: 10.1007/s00439-015-1592-z. Epub 2015 Aug 30.
Through linkage and tagSNP-based association studies in 100 Dominican Republic (DR) families, we previously identified ANLN and AOAH (7p14.3) as candidate genes for carotid intima-media thickness at bifurcation (bIMT). Introns, exons, and flanking regions of ANLN and AOAH were re-sequenced in 151 individuals from nine families with evidence for linkage at 7p14.3. For common variants [CV, minor allele frequency (MAF) ≥5 %], single variant-based analysis was performed. For rare variants (RV, MAF < 5 %), gene-based analysis aggregating all RVs within a gene was performed. CV analysis revealed the strongest signal at rs3815483 (P = 0.0003) in ANLN and rs60023210 (P = 0.00005) in AOAH. In ANLN, RV analysis found suggestive evidence for association with exonic RVs (P = 0.08), and in particular non-synonymous RVs (P = 0.04) but not with all RVs (P = 0.15). The variant alleles of all non-synonymous RVs segregated with the major allele of rs3815483 and were associated with lower bIMT while a novel synonymous RV segregated with the minor allele of rs3815483 and was associated with greater bIMT. Additional analysis in 561 DR individuals found suggestive evidence for association with all ANLN non-synonymous RVs (P = 0.08). In AOAH, no evidence for association with RVs was detected. Instead, conditional analysis revealed that multiple independent intronic CVs are associated with bIMT in addition to rs60023210. We demonstrate the utility of using family-based studies to evaluate the contribution of RVs. Our data suggest two modes of genetic architecture underlying the linkage and association at ANLN (multiple exonic RVs) and AOAH (multiple intronic CVs with uncharacterized functions).
通过对100个多米尼加共和国（DR）家庭进行连锁分析和基于标签单核苷酸多态性（tagSNP）的关联研究，我们之前确定了ANLN和AOAH（7p14.3）作为颈动脉分叉处内膜中层厚度（bIMT）的候选基因。对来自9个在7p14.3处有连锁证据的家庭的151名个体，重新测序了ANLN和AOAH的内含子、外显子及侧翼区域。对于常见变异（CV，次要等位基因频率[MAF]≥5%），进行了基于单个变异的分析。对于罕见变异（RV，MAF<5%），进行了汇总基因内所有RV的基于基因的分析。CV分析显示，ANLN中的rs3815483（P = 0.0003）和AOAH中的rs60023210（P = 0.00005）信号最强。在ANLN中，RV分析发现外显子RV存在关联的提示性证据（P = 0.08），特别是非同义RV（P = 0.04），但并非所有RV都有此关联（P = 0.
15）。所有非同义RV的变异等位基因与rs3815483的主要等位基因共分离，且与较低的bIMT相关，而一个新的同义RV与rs3815483的次要等位基因共分离，且与较高的bIMT相关。在561名DR个体中进行的额外分析发现，所有ANLN非同义RV存在关联的提示性证据（P = 0.08）。在AOAH中，未检测到与RV相关的证据。相反，条件分析显示，除rs60023210外，多个独立的内含子CV与bIMT相关。我们证明了利用基于家系的研究来评估RV贡献的实用性。我们的数据表明，在ANLN（多个外显子RV）和AOAH（多个功能未明的内含子CV）处，连锁和关联背后存在两种遗传结构模式。
