The genetic correlation describes the genetic relationship between two traits and can contribute to a better understanding of the shared biological pathways and/or the causality relationships between ...them. The rarity of large family cohorts with recorded instances of two traits, particularly disease traits, has made it difficult to estimate genetic correlations using traditional epidemiological approaches. However, advances in genomic methodologies, such as genome-wide association studies, and widespread sharing of data now allow genetic correlations to be estimated for virtually any trait pair. Here, we review the definition, estimation, interpretation and uses of genetic correlations, with a focus on applications to human disease.
...the classification and nomenclature of neuromuscular disorders (eg, limb girdle muscular dystrophy, polymyositis, and distal acquired demyelinating symmetric polyneuropathy) were based on these ...observations. ...despite an accurate description of key clinical features, heterogeneous diseases were often grouped together. In 2001, up to 50% of patients with myasthenia gravis who were seronegative for anti-acetylcholine receptor antibodies (anti-AChR) instead were found to have antibodies directed against muscle-specific kinase (anti-MuSK). ...myasthenia gravis was separated into two distinct antibody-mediated diseases. Over the past two decades, single genes and mutations have been shown to have pleiotropic effects—eg, RYR1 mutations can cause core and nemaline myopathy, malignant hyperthermia, and abnormally high serum concentration of creatine kinase in patients who are asymptomatic.6 The phenotypic spectrum of BSCL2 variants in hereditary spastic paraplegias was also extended with detection of mutations in patients with hereditary neuropathies.7 Implementation of gene panels, which typically include more than 100 genes, has meant that a genetic diagnosis can be made in an increasing number of people. ...SMN2 mRNA-splicing-modification therapy and SMN1 gene replacement in patients with hereditary proximal (5q) spinal muscular atrophy are effective and have substantially changed the natural history of individuals with symptomatic14,15 and presymptomatic disease.16 As a result of this success with gene-targeting therapies, the number of therapies targeting single genes with small molecules, antisense oligonucleotides, and viral vectors has grown rapidly.
Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here ...we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 individuals) with associated geography (1,422 individuals). We identify 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. North-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Despite superexponential population growth, regional demographic estimates reveal population crashes contemporaneous with the Black Death. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods.
Objective
The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given ...that treatment options are available now for SMN deficiency.
Methods
In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation‐dependent probe amplification data.
Results
The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston‐Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston‐Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).
Interpretation
In our well‐powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686–697
Abstract A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal ...lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42 ) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10−25 ). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau ( P = .0110) but not Aβ42 suggesting that TREM2 's role in AD may involve tau dysfunction.
Amyotrophic lateral sclerosis (ALS) is considered to be caused by both genetic and environmental factors. The causal cascade is, however, not known. We aimed to assess lifestyle during the ...presymptomatic phase of ALS, stratified by C9orf72 mutation, and examine evidence supporting causality of lifestyle factors.
This study was a longitudinal, population-based, case-control study that used data from the Prospective ALS study the Netherlands. We included patients with a C9orf72 mutation (C9+ group), patients without a C9orf72 mutation (C9– group), and controls. Patients fulfilled the revised El Escorial criteria and were recruited through neurologists and rehabilitation physicians in the Netherlands as well as the Dutch Neuromuscular Patient Association and ALS Centrum website. 1322 population-based controls, matched for age and sex, were enrolled via the patients' general practitioners. Blood relatives or spouses of patients were not eligible as controls. We studied the relationship between ALS risk and smoking, alcohol, physical activity, body-mass index (BMI), and energy intake by the use of structured questionnaires. Smoking, physical activity, and BMI were longitudinally assessed up to 50 years before onset (defined as the period before onset of muscle weakness or bulbar symptoms for cases, or age at completing the questionnaire for controls). We calculated posterior probabilities (P(θ|x)) for causal effects of smoking, alcohol, and BMI, using Bayesian instrumental variable analyses.
Between Jan 1, 2006 and Jan 27, 2016, we included 143 patients in the C9+ group, 1322 patients in the C9– group, and 1322 controls. Compared with controls, cigarette pack-years (C9+ group mean difference from control 3·15, 95% CI 0·36 to 5·93, p=0·027; C9– group 3·20, 2·02 to 4·39, p<0·0001) and daily energy intake at symptom onset (C9+ group 712 kJ, 95% CI 212 to 1213, p=0·0053; C9– group 497, 295 to 700, p<0·0001) were higher in the C9+ and C9– groups, whereas current BMI (C9+ group −2·01 kg/m2, 95% CI −2·73 to −1·29, p<0·0001; C9– group −1·35, −1·64 to −1·06, p<0·0001) and lifetime alcohol consumption (C9+ group −5388 units, 95% CI −9113 to −1663, p=0·0046; C9– group −2185, −3748 to −622, p=0·0062) were lower in the C9+ and C9– groups. Median BMI during the presymptomatic phase for the C9+ group was lower (–0·69 kg/m2, 95% CI −1·24 to −0·13, p=0·015) and physical activity was similar (–348 metabolic equivalent of task MET, 95% CI −966 to 270, p=0·27) to controls, whereas both the median BMI during the presymptomatic phase (0·27 kg/m2, 95% CI 0·04 to 0·50, p=0·022) and physical activity (585 MET, 291 to 878, p=0·0001) were higher in the C9– group than controls. Longitudinal analyses showed more cigarette pack-years in the C9– (starting 47 years pre-onset) and C9+ (starting 24 years pre-onset) groups, and higher physical activity over time in the C9– group (starting >30 years pre-onset). BMI of the C9+ group increased more slowly and was significantly lower (starting at 36 years pre-onset) than in controls, whereas the BMI of the C9– group was higher than controls (23–49 years pre-onset, becoming lower 10 years pre-onset). Instrumental variable analyses supported causal effects of alcohol consumption (P(θ|x)=0·9347) and smoking (P(θ|x)=0·9859) on ALS in the C9– group. We found evidence supporting a causal effect of increased BMI at younger age (mean 33·8 years, SD 11·7) in the C9– group (Pθ|x=0·9272), but not at older ages.
Lifestyle during the presymptomatic phase differs between patients with ALS and controls decades before onset, depends on C9– status, and is probably part of the presymptomatic causal cascade. Identification of modifiable disease-causing lifestyle factors offers opportunities to lower risk of developing neurodegenerative disease.
Netherlands ALS Foundation.
Abstract Previously, we have reported amyotrophic lateral sclerosis (ALS) families with multiple mutations in major ALS-associated genes. These findings provided evidence for an oligogenic basis of ...ALS. In our present study, we screened a cohort of 755 sporadic ALS patients, 111 familial ALS patients (97 families), and 765 control subjects of Dutch descent for mutations in vesicle-associated membrane protein B ( VAPB ). We have identified 1 novel VAPB mutation (p.V234I) in a familial ALS patient known to have a chromosome 9 open reading frame 72 ( C9orf72 ) repeat expansion. This p.V234I mutation was absent in control subjects, located in a region with high evolutionary conservation, and predicted to have damaging effects. Taken together, these findings provide additional evidence for an oligogenic basis of ALS.
The most recent genome-wide association study in amyotrophic lateral sclerosis (ALS) demonstrates a disproportionate contribution from low-frequency variants to genetic susceptibility to disease. We ...have therefore begun Project MinE, an international collaboration that seeks to analyze whole-genome sequence data of at least 15 000 ALS patients and 7500 controls. Here, we report on the design of Project MinE and pilot analyses of successfully sequenced 1169 ALS patients and 608 controls drawn from the Netherlands. As has become characteristic of sequencing studies, we find an abundance of rare genetic variation (minor allele frequency < 0.1%), the vast majority of which is absent in public datasets. Principal component analysis reveals local geographical clustering of these variants within The Netherlands. We use the whole-genome sequence data to explore the implications of poor geographical matching of cases and controls in a sequence-based disease study and to investigate how ancestry-matched, externally sequenced controls can induce false positive associations. Also, we have publicly released genome-wide minor allele counts in cases and controls, as well as results from genic burden tests.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options and an incompletely understood pathophysiology. Although genomewide association studies (GWAS) ...have advanced our understanding of the disease, the precise manner in which risk polymorphisms contribute to disease pathogenesis remains unclear. Of relevance, GWAS have shown that a polymorphism (rs12608932) in the
gene is associated with risk for both ALS and frontotemporal dementia (FTD). Homozygosity for the C-allele at rs12608932 modifies the ALS phenotype, as these patients are more likely to have bulbar-onset disease, cognitive impairment and FTD at baseline as well as shorter survival. UNC13A is expressed in neuronal tissue and is involved in maintaining synaptic active zones, by enabling the priming and docking of synaptic vesicles. In the absence of functional TDP-43, risk variants in
lead to the inclusion of a cryptic exon in
messenger RNA, subsequently leading to nonsense mediated decay, with loss of functional protein. Depletion of
leads to impaired neurotransmission. Recent discoveries have identified
as a potential target for therapy development in ALS, with a confirmatory trial with lithium carbonate in
cases now underway and future approaches with antisense oligonucleotides currently under consideration. Considering
is a potent phenotypic modifier, it may also impact clinical trial outcomes. This present review describes the path from the initial discovery of
as a risk gene in ALS to the current therapeutic options being explored and how knowledge of its distinct phenotype needs to be taken into account in future trials.
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