Genetic insights of all‐cause and vascular dementia through genome‐wide association studies
Authors: Fongang Bernard , Sargurupremraj Muralidharan , Jian Xueqiu , Mishra Aniket , Bis Joshua C , Fan Kang‐Hsien , Li Gloria , Yang Jingyun , Hilal Saima , Knol Maria J. , Concas Maria Pina , Girotto Giorgia , Riaz Moeen , Guðjónsson Alexander , Lacaze Paul , Naj Adam C. , Van Der Lee Sven J. , Skrobot Olivia Anna , Gudnason Vilmundur , Lopez Oscar L. , Haan Mary , Bosnes Ingunn , Dufouil Carole , Ganguli Mary , Cheung Ching‐Lung , Bennett David A , Chen Christopher , Kamboh M. Ilyas , Satizabal Claudia L , Ikram M. Arfan , Debette Stephanie , Fornage Myriam , Yang Qiong , Schellenberg Gerard D. , Winsvold Bendik , Kehoe Patrick G , Ruiz Agustin , Lambert Jean‐Charles , Weinstein Galit , Seshadri Sudha 
Published: December 2022

AbstractBackgroundGenome‐wide association studies (GWAS) have identified more than 40 genetic loci associated with Alzheimer’s disease (AD). Although vascular dementia (VaD) is the second most common type of dementia after AD, the genetic contribution to VaD is understudied. We hypothesize that common forms of dementia will share genetic risk factors. We conducted the largest trans‐ancestral GWAS of "all‐cause dementia" (ACD), VaD, and examined the underlying biological mechanismsMethodDonors from 16 population‐based CHARGE cohorts, two national case‐control consortia (ADGC, MEMENTO), and the UKBB contributed 46,533 and 4,078 cases of ACD and VaD, respectively. The overall sample (475,577) included European, African, Asian, and Hispanic ancestry. We conducted ancestry‐specific and trans‐ancestral meta‐analyses using METAL and MR‐MEGA, respectively. We explored the shared genetics of ACD with related disease traits and risk factors. Using a Bayesian approach, the level of polygenicity is explored across dementia and closely related traits, followed by a multi‐trait GWAS including ACD with traits of identical polygenic background. Finally, genome‐wide (GW) signals were functionally prioritized using a TWAS study.ResultFor ACD, we replicated ten known AD loci, including regions near APOE and BIN1. We found novel suggestive loci near SEMA4D, ANO3, AJAP1, HBEGF, and RBFFOX1. These loci were previously associated with energy transport throughout the brain (SEMA4D), neuronal excitability (ANO3), amyloid plaques (RBFOX1), and cerebral small vessel disease (‐cSVD‐, HBEGF). For VaD, one locus near APOE reached GW significance along with 22 suggestive, including SPRY2, FOXA2, AJAP1, and PSMA3, previously associated with hypertension, diabetes, and neuron maintenance. In addition to the genetic overlap with neurodegenerative processes, genetic risk loci for ACD exhibited overlap with vascular risk factors (T2D, blood pressure, lipid levels) and MRI markers of cSVD. Adjusting for SNP effects from traits with similar polygenic backgrounds revealed risk loci implicated in regulating cholesterol metabolism and maintaining neuronal mRNA levelsConclusionWe leveraged data from 19 cohorts and population‐based studies to assess the genetic contribution to ACD and VaD. GW suggestive signals included genes implicated in various brain activities. Bioinformatic parsing of the identified loci pointed to a genetic overlap of ACD with vascular risk factors and MRI markers of cSVD.