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Late onset Alzheimer’s disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer’s disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer’s Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer’s cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci  PPARGC1A  ( p  = 2.2 × 10 −6 ),  RORA  ( p  = 7.4 × 10 −7 ) and  ZNF423  ( p  = 2.1 × 10 −6 ).  PPARGC1A  and  RORA  are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer’s disease.  PPARGC1A  is additionally linked to energy metabolism and the generation of amyloid beta plaques.  RORA  is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The  ZNF423  gene resides in an Alzheimer’s disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease