Lack of replication of association findings in complex disease: an analysis of 15 polymorphisms in prior candidate genes for sporadic Alzheimer's disease

There is considerable enthusiasm for the prospect of using common polymorph isms (primarily single nucleotide polymorphisms; SNPs) in candidate genes t o unravel the genetics of complex disease. This approach has generated a nu mber of findings of loci which are significantly associated with sporadic A lzheimer's disease (AD). In the present study, a total of 15 genes of inter est were chosen from among the previously published reports of significant association in AD. Genotyping was performed on polymorphisms within those g enes (14 SNPs and one deletion) using Dynamic Allele Specific Hybridization (DASH) in 204 Swedish patients with sporadic late-onset AD and 186 Swedish control subjects. The genes chosen for analysis were; low-density lipoprot ein receptor-related protein (LRP1), angiotensin converting enzyme (DCP1), alpha-2-macroglobulin (A2M), bleomycin hydrolase (BLMH), dihydrolipoyl S-su ccinyltransferase (DLST), tumour necrosis factor receptor superfamily membe r 6 (TNFRSF6), nitric oxide synthase (NOS3), presenilin 1 (PSEN1), presenil in 2 (PSEN2), butyrylcholinesterase (BCHE), Fe65 (APBB1), oestrogen recepto r alpha (ESR1), cathepsin D (CTSD), methylenetetrahydrofolate reductase (MT HFR), and interleukin 1A (IL1A). We found no strong evidence of association for any of these loci with AD in this population. While the possibility ex ists that the genes analysed are involved in AD (ie they have weak effects and/or are population specific), results reinforce the need for extensive r eplication studies if we are to be successful in defining true risk factors in complex diseases.