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Quantifying and modeling birth order effects in autism.

Turner T, Pihur V, Chakravarti A - PLoS ONE (2011)

Bottom Line: We detect statistically significant, yet varying, patterns of birth order effects across these collections.In multiplex families, we identify V-shaped effects where middle births are at high risk; in simplex families, we demonstrate linear effects where risk increases with each additional birth.Moreover, the birth order effect is gender-dependent in the simplex collection.

View Article: PubMed Central - PubMed

Affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Autism is a complex genetic disorder with multiple etiologies whose molecular genetic basis is not fully understood. Although a number of rare mutations and dosage abnormalities are specific to autism, these explain no more than 10% of all cases. The high heritability of autism and low recurrence risk suggests multifactorial inheritance from numerous loci but other factors also intervene to modulate risk. In this study, we examine the effect of birth rank on disease risk which is not expected for purely hereditary genetic models. We analyzed the data from three publicly available autism family collections in the USA for potential birth order effects and studied the statistical properties of three tests to show that adequate power to detect these effects exist. We detect statistically significant, yet varying, patterns of birth order effects across these collections. In multiplex families, we identify V-shaped effects where middle births are at high risk; in simplex families, we demonstrate linear effects where risk increases with each additional birth. Moreover, the birth order effect is gender-dependent in the simplex collection. It is currently unknown whether these patterns arise from ascertainment biases or biological factors. Nevertheless, further investigation of parental age-dependent risks yields patterns similar to those observed and could potentially explain part of the increased risk. A search for genes considering these patterns is likely to increase statistical power and uncover novel molecular etiologies.

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Related in: MedlinePlus

Proportion of observed and expected affected offspring at each birth rank for multiplex families.The data for the numbers of affected offspring for each sibship size and birth order is shown.
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pone-0026418-g006: Proportion of observed and expected affected offspring at each birth rank for multiplex families.The data for the numbers of affected offspring for each sibship size and birth order is shown.

Mentions: Based on the results of power analysis and assumed birth order effects, we can infer that the multiplex collections are not significant for the linear effect (rank-sum test) but very significant for the V-shaped effect (inverse rank-sum test), whereas the SSC showed an opposite pattern. In the combination dataset (AGRE + NIMH), shown in Table 5, we obtained insignificant results for the linear trend but significant results for the V-shaped effect. Thus overall, in both sets of families, the multiplex families are different in their risk profiles across births than the simplex families. Furthermore, in simplex families there is an excess of the affecteds at rank two which is the main driver for the observed birth order effect (Figure 5). On the other hand, in multiplex families the excess at rank 2 is followed by below expected counts in the following birth ranks, contributing to the inverse V-shape effect (Figure 6).


Quantifying and modeling birth order effects in autism.

Turner T, Pihur V, Chakravarti A - PLoS ONE (2011)

Proportion of observed and expected affected offspring at each birth rank for multiplex families.The data for the numbers of affected offspring for each sibship size and birth order is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198479&req=5

pone-0026418-g006: Proportion of observed and expected affected offspring at each birth rank for multiplex families.The data for the numbers of affected offspring for each sibship size and birth order is shown.
Mentions: Based on the results of power analysis and assumed birth order effects, we can infer that the multiplex collections are not significant for the linear effect (rank-sum test) but very significant for the V-shaped effect (inverse rank-sum test), whereas the SSC showed an opposite pattern. In the combination dataset (AGRE + NIMH), shown in Table 5, we obtained insignificant results for the linear trend but significant results for the V-shaped effect. Thus overall, in both sets of families, the multiplex families are different in their risk profiles across births than the simplex families. Furthermore, in simplex families there is an excess of the affecteds at rank two which is the main driver for the observed birth order effect (Figure 5). On the other hand, in multiplex families the excess at rank 2 is followed by below expected counts in the following birth ranks, contributing to the inverse V-shape effect (Figure 6).

Bottom Line: We detect statistically significant, yet varying, patterns of birth order effects across these collections.In multiplex families, we identify V-shaped effects where middle births are at high risk; in simplex families, we demonstrate linear effects where risk increases with each additional birth.Moreover, the birth order effect is gender-dependent in the simplex collection.

View Article: PubMed Central - PubMed

Affiliation: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Autism is a complex genetic disorder with multiple etiologies whose molecular genetic basis is not fully understood. Although a number of rare mutations and dosage abnormalities are specific to autism, these explain no more than 10% of all cases. The high heritability of autism and low recurrence risk suggests multifactorial inheritance from numerous loci but other factors also intervene to modulate risk. In this study, we examine the effect of birth rank on disease risk which is not expected for purely hereditary genetic models. We analyzed the data from three publicly available autism family collections in the USA for potential birth order effects and studied the statistical properties of three tests to show that adequate power to detect these effects exist. We detect statistically significant, yet varying, patterns of birth order effects across these collections. In multiplex families, we identify V-shaped effects where middle births are at high risk; in simplex families, we demonstrate linear effects where risk increases with each additional birth. Moreover, the birth order effect is gender-dependent in the simplex collection. It is currently unknown whether these patterns arise from ascertainment biases or biological factors. Nevertheless, further investigation of parental age-dependent risks yields patterns similar to those observed and could potentially explain part of the increased risk. A search for genes considering these patterns is likely to increase statistical power and uncover novel molecular etiologies.

Show MeSH
Related in: MedlinePlus