Perspectives on the Genomics of HSP Beyond Mendelian Inheritance

Hereditary Spastic Paraplegia is an extraordinarily heterogeneous disease caused by over 50 Mendelian genes. Recent applications of next-generation sequencing, large scale data analysis, and data sharing/matchmaking, have discovered a quickly expanding set of additional HSP genes. Since most recently discovered HSP genes are rare causes of the disease, there is a growing concern of a persisting diagnostic gap, estimated at 30–40%, and even higher for sporadic cases. This missing heritability may not be fully closed by classic Mendelian mutations in protein coding genes. Here we show strategies and published examples of broadening areas of attention for Mendelian and non-Mendelian causes of HSP. We suggest a more inclusive perspective on the potential final architecture of HSP genomics. Efforts to narrow the heritability gap will ultimately lead to more precise and comprehensive genetic diagnoses, which is the starting point for emerging, highly specific gene therapies

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts

Perspectives on the Genomics of HSP Beyond Mendelian Inheritance

Hereditary Spastic Paraplegia is an extraordinarily heterogeneous disease caused by over 50 Mendelian genes. Recent applications of next-generation sequencing, large scale data analysis, and data sharing/matchmaking, have discovered a quickly expanding set of additional HSP genes. Since most recently discovered HSP genes are rare causes of the disease, there is a growing concern of a persisting diagnostic gap, estimated at 30–40%, and even higher for sporadic cases. This missing heritability may not be fully closed by classic Mendelian mutations in protein coding genes. Here we show strategies and published examples of broadening areas of attention for Mendelian and non-Mendelian causes of HSP. We suggest a more inclusive perspective on the potential final architecture of HSP genomics. Efforts to narrow the heritability gap will ultimately lead to more precise and comprehensive genetic diagnoses, which is the starting point for emerging, highly specific gene therapies

Genetic modifiers and non-Mendelian aspects of CMT

Charcot-Marie-Tooth (CMT) neuropathies are amongst the most common inherited diseases in neurology. While great strides have been made to identify the genesis of these diseases, a diagnostic gap of 30-60% remains. Classic models of genetic causation may be limited to fully close this gap and, thus, we review the current state and future role of alternative, non-Mendelian forms of genetics in CMT. Promising synergies exist to further define the full genetic architecture of inherited neuropathies, including affordable whole-genome sequencing, increased data aggregation and clinical collaboration, improved bioinformatics and statistical methodology, and vastly improved computational resources. Given the recent advances in genetic therapies for rare diseases, it becomes a matter of urgency to diagnose CMT patients with great fidelity. Otherwise, they will not be able to benefit from such therapeutic options, or worse, suffer harm when pathogenicity of genetic variation is falsely evaluated. In addition, the newly identified modifier and risk genes may offer alternative targets for pharmacotherapy of inherited and, potentially, even acquired forms of neuropathies

A network biology approach to unraveling inherited axonopathies

Abstract Inherited axonopathies represent a spectrum of disorders unified by the common pathological mechanism of length-dependent axonal degeneration. Progressive axonal degeneration can lead to both Charcot-Marie-Tooth type 2 (CMT2) and Hereditary Spastic Paraplegia (HSP) depending on the affected neurons: peripheral motor and sensory nerves or central nervous system axons of the corticospinal tract and dorsal columns, respectively. Inherited axonopathies display an extreme degree of genetic heterogeneity of Mendelian high-penetrance genes. High locus heterogeneity is potentially advantageous to deciphering disease etiology by providing avenues to explore biological pathways in an unbiased fashion. Here, we investigate ‘gene modules’ in inherited axonopathies through a network-based analysis of the Human Integrated Protein-Protein Interaction rEference (HIPPIE) database. We demonstrate that CMT2 and HSP disease proteins are significantly more connected than randomly expected. We define these connected disease proteins as ‘proto-modules’ and show the topological relationship of these proto-modules by evaluating their overlap through a shortest-path based measurement. In particular, we observe that the CMT2 and HSP proto-modules significantly overlapped, demonstrating a shared genetic etiology. Comparison of both modules with other diseases revealed an overlapping relationship between HSP and hereditary ataxia and between CMT2 + HSP and hereditary ataxia. We then use the DIseAse Module Detection (DIAMOnD) algorithm to expand the proto-modules into comprehensive disease modules. Analysis of disease modules thus obtained reveals an enrichment of ribosomal proteins and pathways likely central to inherited axonopathy pathogenesis, including protein processing in the endoplasmic reticulum, spliceosome, and mRNA processing. Furthermore, we determine pathways specific to each axonopathy by analyzing the difference of the axonopathy modules. CMT2-specific pathways include glycolysis and gluconeogenesis-related processes, while HSP-specific pathways include processes involved in viral infection response. Unbiased characterization of inherited axonopathy disease modules will provide novel candidate disease genes, improve interpretation of candidate genes identified through patient data, and guide therapy development