Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins

Abstract

Background: Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model.

Methods: We assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)).

Results: Among children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e-08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e-09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families.

Conclusions: By classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.

Keywords: AGRE; Female protective model; Interbirth interval; Multiplex families; Recurrence risk; Sex differences.

Figure 1

Recurrence risk for ASD in multiplex families from AGRE by sex and family type. ASD risk to all children born first after the second affected child in each family (N = 456 children from 341 families) is highest for males and in female-containing families. Mosaic plots show the proportion of affected children by (A) sex, (B) family type as FC (female-containing) or MO (male-only), and by (C) sex within each family type. Bar widths are proportional to the number of children or families in each group, which is also noted in the figure. Whiskers note the 95% confidence intervals around each recurrence rate estimate.

Figure 2

Patterns of ASD risk to children born after the multiplex criterion are met. After a family has two affected children, ASD recurrence risk is less for later-born males, particularly those in male-only (MO) families. Line graphs show the proportion of affected children born first and second after a second affected child in all families with at least one subsequent birth by (A) sex, (B) family type as female-containing (FC) or MO, and (C) by sex within each family type. Line plots corresponding to each group are indicated by colors (blue for males, red for females) and solid (female-containing (FC) families) and dashed (male-only (MO) families) lines. The number of families evaluated in each group, the relative risk (RR) to the child born first versus second after the second affected child, and the P value from a two-sided Fisher’s exact test are shown in the tables below each panel. Whiskers note the 95% confidence intervals around each recurrence rate estimate.

Figure 3

Relationship between interbirth interval and ASD recurrence risk by sex and family type. Recurrence risk to subsequent children decreases with increasing interval between births. (A), (B), and (C) show the logistic regression estimated recurrence risk by the number of months since the birth of the second affected child within each subgroup of individuals as indicated by colors (blue for males, red for females) and solid (female-containing (FC) families) and dashed (male-only (MO) families) lines. P values from the whole-model test of logistic regression for affection status given the natural log of interbirth interval (months) are noted; fractions show the number of affected individuals out of the total within the indicated subgroup. (D, E) show the interbirth interval for all evaluated children given their affection status and either their sex (D) or family type (E).

Figure 4

Concordance rates in monozygotic and dizygotic twin pairs classified by their sex. ASD concordance rates are higher for monozygotic than dizygotic twins, and concordance in dizygotic twins shows an effect of sex. (A) Mosaic plot shows the proportion of concordant monozygotic (MZ) twin pairs by the sex of the pair (F-F = female-female, M-M = male-male). Mosaic plots in (B), (C), and (D) show recurrence rates for ASD in co-twins from dizygotic (DZ) twin pairs by co-twin sex (B), proband twin sex (C), and by each combination of proband and co-twin sex (D). Bar widths are proportional to the number of twin pairs in each group, which is also noted in the figure, and whiskers note the 95% confidence intervals around each recurrence risk estimate. Relative risk (RR) and P values for each comparison of interest are also noted in the figure.