Department of Psychology, University of California at Riverside, Riverside, CA 92521, USA.
Hum Mol Genet. 2010 May 15;19(10):2068-78. doi: 10.1093/hmg/ddq079. Epub 2010 Feb 18.
We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.
我们对 25 个可能与脂代谢有关的基因进行了紧密连锁不平衡 (LD) 作图，这些基因位于 1567 例痴呆病例 [包括 1270 例阿尔茨海默病 (AD)] 和 2203 例瑞典对照中。在总共 448 个测试的遗传标记中，最引人注目的关联证据如预期的那样出现在 APOE（rs429358，P 约为 10(-72))，紧随其后的是先前报道的 ABCA1（rs2230805，P 约为 10(-8))。在本研究中，我们报告了另外两个标记，它们位于染色体 17p 上的 SREBF1 基因座附近，在经过多重测试校正后也具有显著意义（最佳 P = 3.1 x 10(-6)，用于标记 rs3183702）。其余基因没有令人信服的关联证据，包括最近全基因组关联研究中血浆脂质的候选基因（CELSR2/PSRC1/SORT1、MLXIPL、PCSK9、GALNT2 和 GCKR）。SREBF1 附近的关联标记位于一个大的 LD 块中，跨越七个候选基因延伸超过 400 kb。跨越 LD 区域的候选基因的表达水平的二次分析以及基因网络背景的研究突出了两个可能的易感基因，包括 ATPAF2 和 TOM1L2。与 rs3183702 紧密连锁的多个标记 (r(2) > 0.7) 被发现与最近的全基因组关联研究中的 AD 风险显著相关，具有相似的效应大小，为目前的发现提供了独立的支持。
