2009在nature genetics的第10期同時發表了兩篇阿爾茨海默氏病 （AD）的全基因組相關性研究（GWAS)，兩項研究集中了歐洲和部分美國的AD研究中心的大量病例，期望能檢測到除APOE以外與AD相關的基因。這兩項研究都發現CLU基因的一個單核苷酸多態性位點（cluster, 作用與APOE相似）與散發阿爾茨海默氏病相關，另外兩個基因CR1（complement component (3b/4b) receptor 1，可能與Aβ的清除相關）和PICALM（phosphatidylinositol-binding clathrin assembly protein gene，參與網格蛋白調節的內吞作用）分別在其中一項研究中達到基因組顯著相關水平，而在另一項中沒有達到，但p值都在10^-2到10^－3之間。
目前發表于JAMA的這項研究用到的European AD Initative和Genetic and Environmental Risk in AD Consortium數據就是來自于去年這兩項研究，研究者將這部分已發表的GWAS數據和他們自己做的數據集中在一起做了meta分析，新發現了兩個與AD相關的位點，并確認了CLU和PICALM與AD的相關性。之后他們在一個獨立的西班牙樣本中驗證了這四個位點與AD的相關性。此外，作者分析了CLU基因和PICALM對預測AD的作用大小。
這項研究分三個階段，第一階段，整合了心臟和衰老基因組流行病學研究協會的基于人群的隊列（1367例AD，973新病例），轉化基因組研究所和Mayo AD GWAS 以前發表的結果，在共3006例AD病例和14642對照中鑒定到了強遺傳相關性（p<10^-3）。有2708個單核苷酸多態性位點（SNPs)的p值小于10^-3。在第二階段，把這些p值小于10^-3SNPs的結果與歐洲AD初步研究（2032病例，5328對照）集中在一起，確認了38個p<10^-5的SNPs(10個位點）。第三階段，組合了這10個遺傳位點與AD遺傳和環境風險因素研究協會的數據，發現4個SNPs位點p值小于1.7*10^-8。 在含1140AD病例和1209例對照的西班牙樣本中重復驗證了這4個位點。全基因組相關性分析完成與2007－2008，薈萃分析和重復確認完成于2009年。
流程如圖所示
這四個位點包括他們首次發現的兩個具有全基因組顯著相關水平位點：BIN1附近的rs744373（OR,1.13， 95％CI：1.06-1.21每次要等位基因拷貝，p=1.59*10^-11)，EXOC3L2/BLOC1S3/MARK4附近的rs597667 （OR, 1.18; 95 CI, 1.07-1.29; P = 6.45x10–9）。雖然在獨立樣本中確定了CLU和PICALM與AD相關，但這兩個基因的位點并沒有改善一個包含年齡，性別和APOE在內的預測AD發病模型的功能（在Rotterdam研究中ROC曲線下面積從0.847提高到0.849，在心血管健康研究中，ROC曲線下面積從0.702提高到0.705）。
雖然這些位點并不能改進我們對AD風險的預測，沒有臨床意義，但他們或許涉及到生物學途徑，在將來基礎研究中起作用。
原文：
Genome-wide Analysis of Genetic Loci Associated With Alzheimer Disease
Context Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).
Objectives To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35 000 persons (8371 AD cases).
Design, Setting, and Participants In stage 1, we identified strong genetic associations (P < 10–3) in a sample of 3006 AD cases and 14 642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P<10–3. In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P<10–5. In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P<1.7x10–8. These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009.
Main Outcome Measure Presence of Alzheimer disease.
Results Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95 confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10–11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95 CI, 1.07-1.29; P = 6.45x10–9). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study).
Conclusions Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.