Genome-wide association study stratified by MAPT haplotypes identifies potential novel loci in Parkinson′s disease

Objective: To identify genetic factors that may modify the effects of the MAPT locus in Parkinson′s disease (PD). Methods: We used data from the International Parkinson′s Disease Genomics Consortium (IPDGC) and the UK biobank (UKBB). We stratified the IPDGC cohort for carriers of the H1/H1 genotype (PD patients n=8,492 and controls n=6,765) and carriers of the H2 haplotype (with either H1/H2 or H2/H2 genotypes, patients n=4,779 and controls n=4,849) to perform genome-wide association studies (GWASs). Then, we performed replication analyses in the UKBB data. To study the association of rare variants in the new nominated genes, we performed burden analyses in two cohorts (Accelerating Medicines Partnership - Parkinson Disease and UKBB) with a total sample size PD patients n=2,943 and controls n=18,486. Results: We identified a novel locus associated with PD among MAPT H1/H1 carriers near EMP1 (rs56312722, OR=0.88, 95%CI= 0.84-0.92, p= 1.80E-08), and a novel locus associated with PD among MAPT H2 carriers near VANGL1 (rs11590278, OR=1.69 95%CI=1.40-2.03, p= 2.72E-08). Similar analysis of the UKBB data did not replicate these results and rs11590278 near VANGL1 did have similar effect size and direction in carriers of H2 haplotype, albeit not statistically significant (OR= 1.32, 95%CI= 0.94-1.86, p=0.17). Rare EMP1 variants with high CADD scores were associated with PD in the MAPT H2 stratified analysis (p=9.46E-05), mainly driven by the p.V11G variant. Interpretation: We identified several loci potentially associated with PD stratified by MAPT haplotype and larger replication studies are required to confirm these associations. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement FRQS, HBHL, CFREF, MJFF, Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of McGill University gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors and the code used in the study is available on github [https://github.com/gan-orlab/PD\_stratified\_GWAS][1] [1]: https://github.com/gan-orlab/PD_stratified_GWAS