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

Abstract

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PDassociated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

Chromosomal inversion polymorphisms shape human brain morphology

“…The exact function of these genes remains to be elucidated, but presumably, they play a role in cellular migration, chemotaxis, and immunity. 48 , 49 Similar to our findings, evidence from several studies indicates that 17q21.31-inv is significantly associated with the expression levels of LRRC37A4P , A2, and A1 in adult samples 9 , 46 , 48 , 50 and fetal brains. 51 , 52 In short, these findings suggest that the inversion has a significant impact on gene regulation.…”

“… 46 , 47 Further, we observed and replicated the significance and effect direction of several LRRC37A copies: core duplicon genes acquired novel promoters and uniquely expanded in primates with unclear gene function, presumably cellular migration, chemotaxis, and immunity. 48 , 49 LRRC37A4P, A2, and A1 have been repeatedly shown to be associated with 17q21.31-inv 9 , 46 , 48 , 50 and have been demonstrated in fetal brains, 51 , 52 though with the cautioning that probes can bind to more than one target genes, especially using earlier array technology. 50 In short, the 17q.21.31-inv with balanced rearrangement does not drastically change gene dosage in the same way as do pathogenic CNVs but rather involves changes in a remarkably diverse range of gene regulatory activity, with downstream impact on normative variation in brain structure and function.…”

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.…”

Distal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancer

“…For overall breast cancer risk, we also detect strong colocalization between eQTLs and GWAS signals at the 17q21.31 locus. This locus houses a large and common inversion polymorphism with associations with breast and ovarian cancer prognosis [94][95][96] , as well as widespread associations with multiple phenotypes, including neuropsychiatric traits, Parkinson's disease, and metabolic traits [97][98][99][100] . In particular, we found that the ncRNA KANSL1-AS1 potentially mediates distal-eQTLs of multiple pcGenes.…”