Opinion
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
The Genetic and Environmental Contributions to Autism Looking Beyond Twins Diana E. Schendel, PhD; Therese K. Grønborg, MSc; Erik T. Parner, MSc, PhD
Autism spectrum disorders (ASDs) are serious neurodevelopmental disorders characterized by difficulties in social interaction and communication accompanied by stereotypical, repetitive behavior and restricted interests. 1 Once considered rare, ASD is now Related article page 1770 reported to affect approximately 1% to 2% of children.2,3 The increase in ASD prevalence in recent decades combined with little understanding of ASD etiology have fostered increases in public and private research funding with a substantial investment in genetic research.4 The historical focus on genetic factors partly arose from evidence from the first twin studies5-7 in which concordance for an ASD diagnosis was reportedly as high as 90% in monozygotic twins and substantially higher than in dizygotic twins. A more recent and larger twin study,8 however, observed a smaller genetic effect and a larger environmental effect on ASD liability than previous work, suggesting that early estimates of the genetic liability for ASD may have been inflated by ascertainment bias.9 Along with twin concordance, another important measure of genetic contribution to disease is familial recurrence. Estimates of sibling recurrence of ASD in families with a previously diagnosed child have ranged from 5.8% to 18.7%,10,11 which are markedly higher than the occurrence of ASD in the general population and thereby support the importance of familial contributions to the risk for ASD. In this issue of JAMA, Sandin and colleagues12 report estimates of both familial recurrence and heritability of ASD based on a large, Swedish population-based birth cohort of more than 2 million children born 1982 through 2006. A total of 14 516 children were diagnosed with ASD, of whom 5689 had autistic disorder. Consistent with the expectation of a significant genetic contribution to ASD, the risk of ASD in family members of persons with ASD was significantly higher than the risk in the general population, and the risk of ASD recurrence among family members decreased with decreasing genetic relatedness, from a 10-fold increased risk of recurrence in full siblings to a 2-fold increased risk of recurrence in cousins. Similarly, the heritability analysis also supported the importance of genetic factors in ASD; the authors suggested that genetic factors explain half of the liability for autism. Using the largest sample size to date, the report by Sandin et al is the first attempt to provide both ASD recurrence and heritability estimates from the same population. Furthermore, for the first time, the authors used family linkage back to grandparents and thereby identified siblings (monozygotic and dizygotic twins and nontwin full and half siblings) 1738
and cousins in order to incorporate extended family relations into the recurrence and heritability estimates. In terms of recurrence, the results for full and half siblings are consistent overall with a recent study based on a Danish populationbased cohort,13 but the new Swedish study was based on a larger sample and, for the first time, considered ASD recurrence among cousins. The heritability results also are generally consistent with a large, California-based twin study8 in terms of observing reduced estimates for genetic liability and increased estimates for environmental effects compared with earlier heritability estimates. The novelty of the Sandin et al study is in the delivery of a single, population-based “package” of results of extended familial risk based on a very large sample. The similarity in results on relative recurrence risks (RRRs) between the present study and the previous Danish populationbased study should be reassuring to parents with a child with ASD who are contemplating having another child. Taking the 2 studies in combination provides a consistently lower benchmark of familial risk for ASD than suggested by several previous smaller studies based on clinical populations. Also reassuring for families is the fact that there is little support for a difference in ASD recurrence according to whether the proband is male or female because in both studies all sibling-sex combinations had similar relative risks of recurrence. In addition, in both studies, spanning births from the early 1980s to the mid-2000s, there was no significant trend in RRRs over time, indicating that the upward trend in autism prevalence over the same period in both populations has either not changed the combination of genetic and environmental factors that contribute to ASD recurrence or not changed the relative magnitude of risk arising from such factors. However, much remains to be understood regarding familial risk for autism. A more complete and perhaps more accurate perspective on familial risk using the recurrence risk approach might be achieved by considering risk for recurrence of underlying ASD-related phenotypic features. Future studies might consider risks from different combinations of diagnoses in the proband and sibling; for example, the risk of any ASD diagnosis in the sibling of a child diagnosed with autistic disorder, or other combinations of ASD-related or comorbid neurodevelopmental diagnoses (eg, ASD-epilepsy combinations). Heritability is defined as the amount of phenotypic variation in a trait in a population that can be attributed to genetic factors as opposed to environmental factors. Although the present study reinforced the heritability find-
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Editorial Opinion
ings from the California twin study8 of a smaller genetic liability and larger environmental component in ASD than reported in earlier studies, unlike that study, it actually observed that genetic and nonshared environmental influences on the liability for ASD and autistic disorder were equally important (and shared environmental factors had a negligible influence). Furthermore, the present study based on extended families estimated an ASD heritability of 50%, whereas another population-based Swedish study based only on twins estimated a heritability of 80%.7 The difference in heritability estimates between the 2 Swedish studies highlights some limitations of the liability threshold models. Although the same underlying model was used in both studies, and both analyses were attempting to estimate the same quantity in a similar population, different results were produced between the twin-based and extended family–based samples. The liability threshold models are simplified genetic models. The models assume that a dichotomous outcome like ASD (yes or no) is derived from an underlying normally distributed trait with some ARTICLE INFORMATION Author Affiliations: Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark (Schendel); Department of Economics and Business, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark (Schendel); Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (Schendel); Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark (Grønborg, Parner). Corresponding Author: Diana E. Schendel, PhD, Section for Epidemiology, Department of Public Health, Aarhus University, Bartholins Allé 2, 8000 Aarhus C, Denmark (diana.schendel@folkesundhed .au.dk). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. World Health Organization. International Statistical Classification of Diseases, 10th Revision (ICD-10). Geneva, Switzerland: World Health Organization; 1992.
threshold value determining presence or absence of the outcome of interest. Furthermore, the models assume that this trait can be decomposed into a sum of different genetic and environmental components (with no interaction between genetic and environmental components) and also assume the degree of correlation among these components depending on the type of familial relation. Incorporating other types of relatives besides twins in the models, as was done in the report in this issue,12 increases sample size (thereby enhancing precision of the estimates) and provides the opportunity to estimate phenotypic variation across families and not just in twins. The assumptions regarding the shared environmental component, however, might be too simplified for extended family data. Altogether, the heritability models are relatively “crude” methods for partitioning genetic vs environmental contributions to ASD. In conclusion, the work by Sandin et al supports appreciation of the importance of genetic factors in ASD and adds substantial impetus to the growing attention to environmental influences in ASD etiology.
2. Elsabbagh M, Divan G, Koh Y-J, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5(3):160-179. 3. Kim YS, Leventhal BL, Koh YJ, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011;168(9):904-912. 4. Singh J, Illes J, Lazzeroni L, Hallmayer J. Trends in US autism research funding. J Autism Dev Disord. 2009;39(5):788-795. 5. Taniai H, Nishiyama T, Miyachi T, Imaeda M, Sumi S. Genetic influences on the broad spectrum of autism: study of proband-ascertained twins. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(6):844-849. 6. Rosenberg RE, Law JK, Yenokyan G, McGready J, Kaufmann WE, Law PA. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch Pediatr Adolesc Med. 2009;163(10):907-914. 7. Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry. 2010;167(11):1357-1363.
among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095-1102. 9. Ronald A, Hoekstra RA. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(3):255-274. 10. Bolton P, Macdonald H, Pickles A, et al. A case-control family history study of autism. J Child Psychol Psychiatry. 1994;35(5):877-900. 11. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):e488-e495. 12. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. doi:10.1001 /jama.2014.4144. 13. Grønborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in fulland half-siblings and trends over time: a population-based cohort study. JAMA Pediatr. 2013;167(10):947-953.
8. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors
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Copyright 2014 American Medical Association. All rights reserved.
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Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
The Genetic and Environmental Contributions to Autism Looking Beyond Twins Diana E. Schendel, PhD; Therese K. Grønborg, MSc; Erik T. Parner, MSc, PhD
Autism spectrum disorders (ASDs) are serious neurodevelopmental disorders characterized by difficulties in social interaction and communication accompanied by stereotypical, repetitive behavior and restricted interests. 1 Once considered rare, ASD is now Related article page 1770 reported to affect approximately 1% to 2% of children.2,3 The increase in ASD prevalence in recent decades combined with little understanding of ASD etiology have fostered increases in public and private research funding with a substantial investment in genetic research.4 The historical focus on genetic factors partly arose from evidence from the first twin studies5-7 in which concordance for an ASD diagnosis was reportedly as high as 90% in monozygotic twins and substantially higher than in dizygotic twins. A more recent and larger twin study,8 however, observed a smaller genetic effect and a larger environmental effect on ASD liability than previous work, suggesting that early estimates of the genetic liability for ASD may have been inflated by ascertainment bias.9 Along with twin concordance, another important measure of genetic contribution to disease is familial recurrence. Estimates of sibling recurrence of ASD in families with a previously diagnosed child have ranged from 5.8% to 18.7%,10,11 which are markedly higher than the occurrence of ASD in the general population and thereby support the importance of familial contributions to the risk for ASD. In this issue of JAMA, Sandin and colleagues12 report estimates of both familial recurrence and heritability of ASD based on a large, Swedish population-based birth cohort of more than 2 million children born 1982 through 2006. A total of 14 516 children were diagnosed with ASD, of whom 5689 had autistic disorder. Consistent with the expectation of a significant genetic contribution to ASD, the risk of ASD in family members of persons with ASD was significantly higher than the risk in the general population, and the risk of ASD recurrence among family members decreased with decreasing genetic relatedness, from a 10-fold increased risk of recurrence in full siblings to a 2-fold increased risk of recurrence in cousins. Similarly, the heritability analysis also supported the importance of genetic factors in ASD; the authors suggested that genetic factors explain half of the liability for autism. Using the largest sample size to date, the report by Sandin et al is the first attempt to provide both ASD recurrence and heritability estimates from the same population. Furthermore, for the first time, the authors used family linkage back to grandparents and thereby identified siblings (monozygotic and dizygotic twins and nontwin full and half siblings) 1738
and cousins in order to incorporate extended family relations into the recurrence and heritability estimates. In terms of recurrence, the results for full and half siblings are consistent overall with a recent study based on a Danish populationbased cohort,13 but the new Swedish study was based on a larger sample and, for the first time, considered ASD recurrence among cousins. The heritability results also are generally consistent with a large, California-based twin study8 in terms of observing reduced estimates for genetic liability and increased estimates for environmental effects compared with earlier heritability estimates. The novelty of the Sandin et al study is in the delivery of a single, population-based “package” of results of extended familial risk based on a very large sample. The similarity in results on relative recurrence risks (RRRs) between the present study and the previous Danish populationbased study should be reassuring to parents with a child with ASD who are contemplating having another child. Taking the 2 studies in combination provides a consistently lower benchmark of familial risk for ASD than suggested by several previous smaller studies based on clinical populations. Also reassuring for families is the fact that there is little support for a difference in ASD recurrence according to whether the proband is male or female because in both studies all sibling-sex combinations had similar relative risks of recurrence. In addition, in both studies, spanning births from the early 1980s to the mid-2000s, there was no significant trend in RRRs over time, indicating that the upward trend in autism prevalence over the same period in both populations has either not changed the combination of genetic and environmental factors that contribute to ASD recurrence or not changed the relative magnitude of risk arising from such factors. However, much remains to be understood regarding familial risk for autism. A more complete and perhaps more accurate perspective on familial risk using the recurrence risk approach might be achieved by considering risk for recurrence of underlying ASD-related phenotypic features. Future studies might consider risks from different combinations of diagnoses in the proband and sibling; for example, the risk of any ASD diagnosis in the sibling of a child diagnosed with autistic disorder, or other combinations of ASD-related or comorbid neurodevelopmental diagnoses (eg, ASD-epilepsy combinations). Heritability is defined as the amount of phenotypic variation in a trait in a population that can be attributed to genetic factors as opposed to environmental factors. Although the present study reinforced the heritability find-
JAMA May 7, 2014 Volume 311, Number 17
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of California - Davis User on 05/11/2014
jama.com
Editorial Opinion
ings from the California twin study8 of a smaller genetic liability and larger environmental component in ASD than reported in earlier studies, unlike that study, it actually observed that genetic and nonshared environmental influences on the liability for ASD and autistic disorder were equally important (and shared environmental factors had a negligible influence). Furthermore, the present study based on extended families estimated an ASD heritability of 50%, whereas another population-based Swedish study based only on twins estimated a heritability of 80%.7 The difference in heritability estimates between the 2 Swedish studies highlights some limitations of the liability threshold models. Although the same underlying model was used in both studies, and both analyses were attempting to estimate the same quantity in a similar population, different results were produced between the twin-based and extended family–based samples. The liability threshold models are simplified genetic models. The models assume that a dichotomous outcome like ASD (yes or no) is derived from an underlying normally distributed trait with some ARTICLE INFORMATION Author Affiliations: Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark (Schendel); Department of Economics and Business, National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark (Schendel); Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (Schendel); Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark (Grønborg, Parner). Corresponding Author: Diana E. Schendel, PhD, Section for Epidemiology, Department of Public Health, Aarhus University, Bartholins Allé 2, 8000 Aarhus C, Denmark (diana.schendel@folkesundhed .au.dk). Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. REFERENCES 1. World Health Organization. International Statistical Classification of Diseases, 10th Revision (ICD-10). Geneva, Switzerland: World Health Organization; 1992.
threshold value determining presence or absence of the outcome of interest. Furthermore, the models assume that this trait can be decomposed into a sum of different genetic and environmental components (with no interaction between genetic and environmental components) and also assume the degree of correlation among these components depending on the type of familial relation. Incorporating other types of relatives besides twins in the models, as was done in the report in this issue,12 increases sample size (thereby enhancing precision of the estimates) and provides the opportunity to estimate phenotypic variation across families and not just in twins. The assumptions regarding the shared environmental component, however, might be too simplified for extended family data. Altogether, the heritability models are relatively “crude” methods for partitioning genetic vs environmental contributions to ASD. In conclusion, the work by Sandin et al supports appreciation of the importance of genetic factors in ASD and adds substantial impetus to the growing attention to environmental influences in ASD etiology.
2. Elsabbagh M, Divan G, Koh Y-J, et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 2012;5(3):160-179. 3. Kim YS, Leventhal BL, Koh YJ, et al. Prevalence of autism spectrum disorders in a total population sample. Am J Psychiatry. 2011;168(9):904-912. 4. Singh J, Illes J, Lazzeroni L, Hallmayer J. Trends in US autism research funding. J Autism Dev Disord. 2009;39(5):788-795. 5. Taniai H, Nishiyama T, Miyachi T, Imaeda M, Sumi S. Genetic influences on the broad spectrum of autism: study of proband-ascertained twins. Am J Med Genet B Neuropsychiatr Genet. 2008;147B(6):844-849. 6. Rosenberg RE, Law JK, Yenokyan G, McGready J, Kaufmann WE, Law PA. Characteristics and concordance of autism spectrum disorders among 277 twin pairs. Arch Pediatr Adolesc Med. 2009;163(10):907-914. 7. Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H. The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry. 2010;167(11):1357-1363.
among twin pairs with autism. Arch Gen Psychiatry. 2011;68(11):1095-1102. 9. Ronald A, Hoekstra RA. Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet. 2011;156B(3):255-274. 10. Bolton P, Macdonald H, Pickles A, et al. A case-control family history study of autism. J Child Psychol Psychiatry. 1994;35(5):877-900. 11. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):e488-e495. 12. Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A. The familial risk of autism. JAMA. doi:10.1001 /jama.2014.4144. 13. Grønborg TK, Schendel DE, Parner ET. Recurrence of autism spectrum disorders in fulland half-siblings and trends over time: a population-based cohort study. JAMA Pediatr. 2013;167(10):947-953.
8. Hallmayer J, Cleveland S, Torres A, et al. Genetic heritability and shared environmental factors
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Copyright 2014 American Medical Association. All rights reserved.
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