Alzheimer's disease is a genetically complex disorder; rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been shown to as much as triple an individual's risk of ...developing Alzheimer's disease. TREM2 is a transmembrane receptor expressed in cells of the myeloid lineage, and its association with Alzheimer's disease supports the involvement of immune and inflammatory pathways in the cause of the disease, rather than as a consequence of the disease. TREM2 variants associated with Alzheimer's disease induce partial loss of function of the TREM2 protein and alter the behaviour of microglial cells, including their response to amyloid plaques. TREM2 variants have also been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and frontotemporal dementia. Although the low frequency of TREM2 variants makes it difficult to establish robust genotype–phenotype correlations, such studies are essential to enable a comprehensive understanding of the role of TREM2 in different neurological diseases, with the ultimate goal of developing novel therapeutic approaches.
The search for rare variants in Alzheimer's disease (AD) is usually deemed a high-risk - high-reward situation. The challenges associated with this endeavor are real. Still, the application of ...genome-wide technologies to large numbers of cases and controls or to small, well-characterized families has started to be fruitful.Rare variants associated with AD have been shown to increase risk or cause disease, but also to protect against the development of AD. All of these can potentially be targeted for the development of new drugs.Multiple independent studies have now shown associations of rare variants in NOTCH3, TREM2, SORL1, ABCA7, BIN1, CLU, NCK2, AKAP9, UNC5C, PLCG2, and ABI3 with AD and suggested that they may influence disease via multiple mechanisms. These genes have reported functions in the immune system, lipid metabolism, synaptic plasticity, and apoptosis. However, the main pathway emerging from the collective of genes harboring rare variants associated with AD is the Aβ pathway. Associations of rare variants in dozens of other genes have also been proposed, but have not yet been replicated in independent studies. Replication of this type of findings is one of the challenges associated with studying rare variants in complex diseases, such as AD. In this review, we discuss some of these primary challenges as well as possible solutions.Integrative approaches, the availability of large datasets and databases, and the development of new analytical methodologies will continue to produce new genes harboring rare variability impacting AD. In the future, more extensive and more diverse genetic studies, as well as studies of deeply characterized families, will enhance our understanding of disease pathogenesis and put us on the correct path for the development of successful drugs.
Over the past five years the field of neurogenetics has yielded a wealth of data that have facilitated a much greater understanding of the aetiology of many neurological diseases. Most of these ...advances are a result of improvements in technology that have allowed us to determine whole-genome structure and variation and to examine its impact on phenotype in an unprecedented manner. Genome-wide association studies have provided information on how common genetic variability imparts risk for the development of various complex diseases. Moreover, the identification of rare disease-causing mutations have led to the discovery of novel biochemical pathways that are involved in disease pathogensis. Here, we review these advances and discuss how they have changed the approaches being used to study neurological disorders.
In just over a decade, advances in genome-wide association studies (GWAS) have offered an approach to stratify individuals based on genetic risk for disease. Using recent Alzheimer's disease (AD) ...GWAS results as the base data, we determined each individual's polygenic risk score (PRS) in the UK Biobank dataset. Using individuals within the extreme risk distribution, we performed a GWAS that is agnostic of AD phenotype and is instead based on known genetic risk for disease. To interpret the functions of the new risk factors, we conducted phenotype analyses, including a phenome-wide association study. We identified 246 loci surpassing the significance threshold of which 229 were not reported in the base AD GWAS. These include loci that showed suggestive levels of association in the base GWAS and loci not previously suspected to be associated with AD. Among these, there are loci, such as IL34 and KANSL1, that have since been shown to be associated with AD in recent studies. We also show highly significant genetic correlations with multiple health-related outcomes that provide insights into prodromal symptoms and comorbidities. This is the first study to utilize PRS as a phenotype-agnostic group classification in AD genetic studies. We identify potential new loci for AD and detail phenotypic analysis of these PRS extremes.
Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature ...death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease.
Patients infected with severe acute respiratory syndrome coronavirus 2 might have bacterial and fungal superinfections develop. We describe a clinical case of coronavirus disease with pulmonary ...aspergillosis associated with Bordetella hinzii pneumonia in an immunocompetent patient in France. B. hinzii infections are rare in humans and develop secondary to immunosuppression or debilitating diseases.
The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative ...analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase (FAAH) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH-based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.
Frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and vascular dementia (VaD) are the most common forms of dementia after Alzheimer's disease (AD). The heterogeneity of these disorders ...and/or the clinical overlap with other diseases hinder the study of their genetic components. Even though Mendelian dementias are rare, the study of these forms of disease can have a significant impact in the lives of patients and families and have successfully brought to the fore many of the genes currently known to be involved in FTD and VaD, starting to give us a glimpse of the molecular mechanisms underlying these phenotypes. More recently, genome-wide association studies have also pointed to disease risk-associated loci. This has been particularly important for DLB where familial forms of disease are very rarely described. In this review we systematically describe the Mendelian and risk genes involved in these non-AD dementias in an effort to contribute to a better understanding of their genetic architecture, find differences and commonalities between different dementia phenotypes, and uncover areas that would benefit from more intense research endeavors.
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