What Is the Chance That You Will Get Familial Als
PLoS 1. 2011; six(11): e27985.
The Heritability of Amyotrophic Lateral Sclerosis in a Clinically Ascertained United States Research Registry
Thomas S. Wingo
1 Atlanta Veterans Administration Medical Eye, Atlanta, Georgia, U.s. of America,
2 Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, United States of America,
David J. Cutler
3 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United states of america of America,
Nicole Yarab
2 Department of Neurology, Emory University Schoolhouse of Medicine, Atlanta, Georgia, United states of america of America,
Crystal M. Kelly
ii Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, United States of America,
Jonathan D. Glass
ii Department of Neurology, Emory University Schoolhouse of Medicine, Atlanta, Georgia, U.s.a.,
Marking R. Cookson, Editor
Received 2011 Sep ii; Accepted 2011 Oct 28.
Abstruse
Background
The genetic basis of amyotrophic lateral sclerosis (ALS) is not entirely articulate. While there are families with rare highly penetrant mutations in Cu/Zn superoxide dismutase 1 and several other genes that cause apparent Mendelian inheritance of the disease, most ALS occurs in families without another afflicted individual. However, twin studies suggest that all ALS has a substantial genetic basis. Herein, nosotros estimate the genetic contribution to ALS in a clinically ascertained case series from the United States.
Methodology/Principal Findings
We used the database of the Emory ALS Heart to define individuals with ALS forth with their family unit histories to decide the concordance among parents and offspring for the disease. We constitute that concordance for all parent–offspring pairs was depression (<2%). With this concordance we found that ALS heritability, or the proportion of the disease explained by genetic factors, is betwixt xl and 45% for all likely estimates of ALS lifetime prevalence.
Conclusions/Significance
We found the lifetime chance of ALS is 1.one% in first-caste relatives of those with ALS. Environmental and genetic factors appear near as important for the development of ALS.
Introduction
Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease or Lou Gehrig's disease) is a progressive and fatal degenerative illness of motor neurons. The genetic basis of ALS is not known; withal, familial clustering of ALS has suggested a genetic basis for the disease. In population-based studies, between 1.half dozen% and 5.6% of individuals with ALS take a relative with ALS [1], [2]. Families with ALS ofttimes bear witness autosomal dominant manual, although autosomal recessive pedigrees are as well described. Nearly 20% of individuals with familial ALS bear mutations in the gene Cu/Zn superoxide dismutase i (SOD1) [iii]. Mutations in other genes accept also been described [4], [v]. Thus it is clear that some ALS cases have a strong genetic basis, merely these families account for fewer than 10% of all ALS cases. However, the verbal caste inherited genetic factors play in evolution of ALS overall remains an open question.
2 studies take addressed this question using concordance for ALS among twins, but the conclusions may be limited past the modest numbers of patients included and overlapping samples [half-dozen], [vii]. The British motor neuron affliction (MND) twin study found ALS heritability to be betwixt 38 and 85%, using 76 twin pairs [vii]. A more than recent study included 171 twin pairs by combining the British MND data with data from twins identified via an ALS registry in the United Kingdom and from the National Swedish Twin Registry [6]. This study plant the heritability of ALS to be 76% (95% confidence interval, 60–86%) when individuals with familial forms (i.e. known ALS in other non-twin family unit members) of the affliction were included. Nonetheless, when familial cases were excluded, the heritability of ALS dropped to 61% (95% confidence interval, 38–78%).
Here we approached the heritability of ALS by examining the concordance among ALS patients (probands) and their parents, using a clinically ascertained population from a single ALS clinical center. This approach is not traditional since we are ascertaining offspring and examining the risk among their parents; however, it is mathematically equivalent to the traditional method of parent-offspring heritability studies where the parent is the proband and allows larger numbers of probands to exist examined, enhancing the power of the analysis. Additionally, unlike concordance among twins, concordance among parents and offspring is unlikely to change with time since the majority of parents are deceased past the time their offspring develop ALS, given the mean age of ALS onset is approximately 60 years old [8], [nine], [ten]. Because the worldwide annual incidence is adequately uniform at approximately one–2.5 cases per 100,000, (with the notable exception of a historical higher incidence in Guam thought to be due to unique environmental influences in that region [xi]), we were able to approximate ALS heritability for all plausible estimates of ALS prevalence. These estimates as well have into consideration the slight male predominance of ALS [nine], [10], [12].
Methods
Objective
Our objective was to guess the heritability of ALS using the prevalence amongst relatives ascertained from the Emory ALS Clinic in the United states.
Participants
Probands were ascertained from a example series database collected by the Emory ALS Center from December 1997 to March 2011. All individuals completed a standardized history that included detailed questions on family history of ALS, a thorough neurologic and neuromuscular test, and/or electrophysiologic investigation. Family history was obtained both by a questionnaire and verified at the initial interview by a clinician. Inclusion criteria were the diagnosis of ALS and non-missing parental family history data. Only the starting time identified family unit fellow member was included when multiple afflicted individuals in a family were bachelor.
Concordance for ALS among Relatives
Participants indicated whether their parents had ALS. When possible the affected parents were examined at the Emory ALS Middle. Alternatively, the medical records, including md notes and autopsy records, were obtained to establish the diagnosis in the parents. We defined a concordant parent-offspring pair as a proband with clinical ALS and a parent with ALS as determined using the all-time available evidence.
Estimating ALS Heritability
We determined sexual activity–specific concordance rates among all combinations of parent–offspring pairs (i.east., father–daughter, father–son, mother–girl, and female parent–son). To estimate ALS heritability, we followed the methods of Falconer [xiii], and assumed the beingness of a ordinarily distributed latent liability to ALS in the general population. Liability in this model refers to all possible ecology and genetic influences on the evolution of ALS; individuals beyond a sure liability threshold develop ALS, while those below the threshold exercise not. The threshold was set using the lifetime prevalence of ALS for the full general population. For our model this is the lifetime ALS prevalence among the parents' generation. Since nosotros practise not know the lifetime prevalence of ALS in the full general population, i.eastward. amid the parents' generation, we first estimated heritability for all likely values of ALS lifetime prevalence taken from the literature, and so came upwards with point estimates from widely cited prevalence estimates of ALS.
Statistical Assay
Heritability was calculated for each combination of parent and offspring genders independently. Starting time, we used our estimate of the lifetime prevalence of ALS for each gender to gear up the liability threshold for that disease (x) and hateful deviate of affected individuals (a). The threshold and hateful deviate were calculated for each sex-specific parent-offspring pair. A parent-offspring regression coefficient (b) (half heritability) was obtained using the post-obit equation [13]:
Here the subscripts thou and r refer to the sexual activity-specific prevalence from the general population (i.e., proband'due south sex) or relative (i.e., parent'due south sexual activity), respectively. The sampling variance of the regression coefficient [13] is given past:
West refers to the prevalence, and the subscripts g and r refer to the sex-specific prevalence from the general population or relative, respectively. Heritability (htwo) for parent-offspring pairs is [13]:
The standard error of heritability is [13]:
Mean heritability and standard error were calculated weighted by the reciprocal of the sampling variance for each parent-offspring pair.
Ethics
The Emory University Institutional Review Board approved of the study, and all participants gave informed consent to be in the Emory Clinical Research in Neurology Registry.
Results
From the Emory ALS enquiry database we ascertained 1088 probands with ALS and parental data. Fourteen probands were excluded from assay considering of lack of information about parental medical history. The demographics of the report population are given in table one. The demographic characteristics of our ALS population was similar to that reported from other example series and population-based studies [viii], [ix] with male person predominance of 1.45∶1, and a mean historic period of onset of 58 years erstwhile.
Tabular array 1
Demographics.
| n = 1088 | |
| Sex activity | |
| Female (%) | 452 (41.5) |
| Male (%) | 636 (58.v) |
| Raceone | |
| American Indian (%) | ane (0.2) |
| Asian (%) | 6 (1.2) |
| Black (%) | 80 (fifteen.7) |
| White (%) | 421 (82.9) |
| Mean Historic period of Onset (years ± SD)two | 58±12.7 |
| First Symptoms3 | |
| Bulbar (%) | 279 (27.5) |
| Diaphragm or Other (%) | 11 (one.1) |
| Lower Extremity (%) | 364 (35.9) |
| Upper Extremity (%) | 361 (35.half dozen) |
Among the entire cohort, 45 individuals (4.1%) had a family history of ALS. However, only 24 patients (2.2%) had an affected parent. Interestingly, iii individuals had affected siblings and no afflicted parents, i had an affected child and a second-degree relative, and the remaining 17 had second-caste relatives afflicted. The parent-offspring cyclopedia is shown by gender for all probands in table 2. For all parent-offspring pairs, the cyclopedia was less than 2%. Concordance was least (0.5%, or 1 of 452 parent-offspring pairs) among fathers of affected women.
Tabular array 2
Parent-Offspring Concordance for ALS.
| Father | Mother | |||
| Percent Concordance | Concordant/Total | Percentage Cyclopedia | Concordant/Total | |
| Female Proband | 0.22% | ane / 452 | one.8% | 8 / 452 |
| Male person Proband1 | 1.1% | 7 / 635 | 1.iii% | 8 / 636 |
To estimate the heritability of a trait, we must know the prevalence of the trait among relatives and the general population. Since we do non know the prevalence of ALS in the general population with certainty, we estimated the heritability for ALS using a range of likely male person and female ALS prevalence values. We plant that for all lifetime prevalence values less than 500 per 100,000 for men and 300 per 100,000 for women, ALS heritability is between 27 and 73%. These results are graphically displayed in figure 1. Next, we estimated ALS heritability for probable values of ALS lifetime prevalence in the Us, assuming an boilerplate lifespan of seventy years for men and 75 years for women for our cohort'due south parents. From the literature nosotros found estimates for ALS lifetime prevalence for men and women that ranged from 150–250 per 100,000 for men anile 70 years and 80–220 per 100,000 for women anile 75 years [14]. Using these values nosotros calculated ALS heritability to exist between 36 and 48%. We establish a slightly higher ALS heritability of fifty.viii% (95% confidence interval, 41.4–60.2%) by computing the lifetime prevalence from the estimated annual incidence charge per unit of ∼ii.0 per 100,000 in the United States [ix], [15]. These analyses atomic number 82 the states to conclude that genetic factors contribute betwixt 40 and 60% to the risk for developing ALS. To refine these estimates we note that nether a polygenic model of disease, heritability should be equal for each pair of parent and offspring; withal, nosotros found that the observed value of father-girl pairs is significantly lower than expected for any heritability above 45% (p = 0.01), implying 45% is an upper bounds for ALS heritability.
Heritability of Amyotrophic Lateral Sclerosis.
A contour plot of the ALS heritability as a part of male person and female lifetime ALS prevalence. The bar on the correct shows the color lawmaking for the respective heritability value. The black lines on the graph evidence the boundaries for heritability values given by the corresponding number to a higher place the line.
To examine the potential confounding role of ethnicity in our cohort, we estimated the heritability among self-identified white individuals lone. This group was chosen because it comprises the majority (82.nine%) of the individuals for whom we accept ethnicity information. Using the lifetime ALS prevalence of 200 per 100,000, we found ALS heritability is 58.1% (95% CI: 45.0–71.2%), similar to what nosotros establish for the unabridged cohort.
Discussion
We assessed the gamble of ALS among parents of affected individuals in a large case series ascertained from the Emory ALS Center. We found that the run a risk for ALS among showtime-degree relatives is 1.1%, which is similar to two other studies that estimated parent-offspring risk by examining children of affected individuals [16], [17] and implies the relative risk amongst first-degree relatives is 2.2–vi.9, depending on the true lifetime prevalence of ALS in the United States. Our data also suggests that inherited factors account for roughly one-half of the liability for developing ALS, bold no shared environmental factors. Surprisingly, we found significantly (p = 0.01) fewer concordant female person probands and father pairs than expected for heritability values higher up 45%. At that place is no elementary genetic model that explains this finding (due east.k., autosomal dominant, recessive, X-linked, or mitochondrial), and nether the polygenic model, this group should accept the highest proportion of concordant parent-offspring pairs (instead of the lowest), because ALS is more than prevalent in males than females [xiii]. Recollect that in our experiment the probands are the offspring. Thus, father-daughters pairs should exhibit the highest concordance considering the risk of ALS is lower in women, causing affected daughters to exist shifted further from the mean female liability for ALS than affected sons are from the mean male liability. The consequence of affected daughters having a higher liability is that her parents are more likely to have had ALS, specially fathers since the take a chance for ALS is higher in men. While any conclusions from these information must be tempered past the relatively small number of afflicted parent-offspring pairs, these data do advise that either the heritability of ALS is less than or equal to 45%, or that ALS is not a significantly polygenic disease. Indeed, there is testify from the literature that there may be relatively few genetic causes that contribute to ALS considering the recent identification of the hexamer repeat in C9ORF72 and well-described SOD1 mutations that account for a substantial proportion of familial and sporadic ALS cases [4], [18], [19]. Nevertheless, we find no convincing alternative to the polygenic model of disease based on the observed concordance among our cohort. Other plausible explanations are that people by and large know less about the medical health history of their male parent than their mother, which is suggested by the general tendency of lower father-offspring cyclopedia for both male and female probands observed in the data, or that our case series is not reflective of ALS in the full general population. However, we note that our population has a similar hateful historic period of onset and prevalence of familial ALS as reported for other population-based ALS studies [i], [8]. In our view, the nigh likely explanation of the information is just that the heritability of ALS is between forty and 45%. This is best seen in figure 1, which shows ALS heritability for all plausible values of ALS lifetime prevalence. The ii prior European studies constitute a college signal estimate of ALS heritability, simply our estimate of 40% is contained within their 95% confidence intervals [6], [vii]. The dissimilar values may just reverberate a true difference betwixt the relative contribution of environmental and genetic factors, or differences in lifetime prevalence of ALS between the written report locations. In either case, our findings advise ALS has roughly equivalent contribution from genetic and environmental factors.
Our study has several strengths. Commencement, we analyzed a large accomplice of clinically ascertained cases of ALS. Family unit histories, including pedigrees, were prospectively ascertained on all individuals. The bulk of patients had deceased parents and thus concordance for ALS is unlikely to alter with time. 1 possible concern in our study is ascertainment bias of individuals with a stronger family unit history, i.due east. the probability of ascertaining a proband with family history of ALS is college than those without family history. In this scenario, our results would probable deviate from what we would look nether a polygenic model of affliction; however, incomplete ascertainment of families with ALS could too pb to acceptance of a polygenic model when it should be rejected [20], [21]. In our view, referral bias (or incomplete ascertainment of families) seems unlikely, because the depression number of familial ALS cases (4.one%) in our cohort that is similar to what is seen in population-based studies of ALS that institute one.half dozen–v.6% familial ALS [i], [2]. Another potential weakness is that we do non know the exact prevalence of ALS in the general population, which we addressed by using a broad range of likely ALS lifetime prevalence values amongst men and women.
In summary, we found ALS has a moderate genetic footing, with a likely heritability between twoscore and 45%. It is noteworthy that in our cohort nearly one-half of all concordant parent-offspring pairs are due to known SOD1 mutations, probably because patients with a family history of ALS undergo SOD1 mutation screening. This raises the question of how much of ALS heritability is explained entirely by SOD1 mutations, which should exist the focus of future investigations.
Acknowledgments
We acknowledge the hard work of Meraida Polak, R.N., Jaffar Khan, G.D., and the staff of the Emory ALS Center in ascertaining patient data and maintaining the ALS database. Nosotros are grateful to the patients and families with ALS who agreed to participate in this study.
Footnotes
Competing Interests: The authors have declared that no competing interests exist.
Funding: TSW is supported by a career development grant by the Department of Veterans Affairs (CDA1-002-09F). This study does non have any specific funding, and the Department of Veteran Affairs had no office in study blueprint, data collection and analysis, conclusion to publish, or preparation of the manuscript.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222666/
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