Running Head : GWAS Meta-Analysis of Alzheimer ’ s Disease 1 Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer ’ s disease risk

Late onset Alzheimer’s disease (AD) is the most common form of dementia with more than 35 million people affected worldwide, and no curative treatment available. AD is highly heritable and recent genome-wide meta-analyses have identified over 20 genomic loci associated with AD. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci exist. Here, we performed the largest genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 AD cases, 383,378 controls). AD-by-proxy status is based on parental AD diagnosis and showed strong genetic correlation with AD (rg=0.81). Genetic meta-analysis identified 29 risk loci, of which 9 are novel, and implicating 215 potential causative genes. Independent replication further supports these novel loci in AD. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver and microglia). Furthermore, gene-set analyses indicate the genetic contribution of biological mechanisms involved in lipidrelated processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomisation results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying more of the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD to guide new drug development. Main text Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with roughly 35 million people affected.1 Results from twin studies indicate that AD is highly heritable, with estimates ranging between 60 and 80%.2 Genetically, AD can be roughly divided into 2 subgroups: 1) familial