17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Abstract

Background Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. Methods To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. Results We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. Conclusion These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

Functional regulatory variants implicate distinct transcriptional networks in dementia

“…The chromosome 17q21.31 locus is noteworthy for harboring the tau-encoding MAPT gene within a common 900-kb inversion polymorphism and is a major risk locus for PSP (H1 haplotype OR = 4 to 5) as well as AD, Parkinson’s disease, and corticobasal degeneration ( 10 ). 17q21.31 contains complex haplotypic substructural variation and extensive LD, hampering interrogation with traditional statistical genetics approaches ( 13 ).…”

“…These variants were of interest because tau pathology within oligodendrocytes is a defining pathological feature of PSP ( 40 ). All eight of these regulatory variants are in low LD ( D ′ = 1, R 2 = 0.18) with rs242557, a marker SNP for the H1C subhaplotype known to confer risk for PSP ( 10 ) (data S4 shows pairwise LD for rs242557).…”

“…Most of these loci overlap noncoding regions and encompass hundreds of variants that are difficult to study owing to linkage disequilibrium (LD), which hampers the identification of underlying regulatory variants and associated risk genes ( 9 ). Salient examples include regions harboring multiple independent association signals, such as the H1 pan-neurodegenerative risk haplotype at 17q21.31 that includes the MAPT locus ( 10 ) and the AD risk locus at 19q13.32 that harbors APOE ( 11 , 12 ) .…”

Inter-individual variation in human cortical cell type abundance and expression

“…LRRC37A shows lower expression in temporal and frontal cortex of individuals with H1 vs. H2 haplotype in populations with European ancestry ( 61 ), suggesting a possible protective effect. In fact, a recent study on Parkinson’s disease linked protective sub-haplotypes of this locus with increased expression of LRRC37A in brain, although LRRC37A was primarily expressed in astrocytes in the substantia nigra ( 76 ). Although further work is needed to disentangle the effects of LRRC37A in neurons vs. astrocytes, and to see whether increased LRRC37A expression is likewise protective in other tauopathies, our results point to LRRC37A and ARL17B as important candidates for consideration in future studies of neurodegeneration.…”

The influence of 17q21.31 and APOE genetic ancestry on neurodegenerative disease risk

“…While these data indicate the presence of ancestry-specific variants of MAPT , the association with PD risk is less convincing; this is unsurprising given that the GWAS association in European populations spans a ∼1 Mb region, which incorporates numerous genes other than MAPT . There is also limited evidence that the 17q21.31 signal implicates MAPT as the causative gene, but rather recent studies favor KANSL1 , CRHR1 , or LRRC37A2 as likely candidates contributing to PD risk ( Loesch et al, 2021 ; Yao et al, 2021 ; Bowles et al, 2022 ). The contribution of rare variants in these specific genes has not yet been investigated in any population.…”