Sex differences in autism spectrum disorders

In the paper

“thereby implicating specific CNV loci in ASD liability”

What the sources say

• Supported

  The Discussion reports strong evidence that duplications at 7q11.23 contribute to ASD and identifies additional recurrent CNV loci, including 16p13.2 and CDH13. This supports the claim that specific CNV loci are implicated in ASD liability. (LLM, conf=0.93)

  cites [47] source

In the paper

“Co-morbid ID increases females’ likelihood of acquiring an ASD diagnosis, and conversely high-functioning females may go undiagnosed.”

In the paper

“a 1999 review reported median sex ratios of 6:1 among normal-functioning subjects and 1.7:1 among cases with moderate to severe ID [11].”

What the sources say

• Not checked yetcites [11] Fombonne E The epidemiology of autism: a review Psychol Med 1999 29 4 769 86 10473304 source

In the paper

“The wide variation in the sex ratio reported by different sites in the Autism and Developmental Disabilities Monitoring (ADDM) Network and findings from large-scale population screening for ASD in a South Korean community where clinically ascertained samples show higher M:F ratios than less biased population screening are consistent with this hypothesis [12**,13**].”

What the sources say

• Not checked yetcites [12**,13**]

In the paper

“we currently do not understand the extent of this over-representation, or the degree to which this male bias in prevalence is related to intellectual functioning or ascertainment methods in addition to the influence of sex-differential genetic or hormonal factors.”

In the paper

“Intelligence level affects this sex ratio: males are substantially over-represented among high-functioning cases, and males and females are more equally represented among cases with severe intellectual disability (ID) [8,9,10,11]”

What the sources say

• Not checked yetcites [8] Volkmar FR Szatmari P Sparrow SS Sex differences in pervasive developmental disorders J Autism Dev Disord 1993 23 4 579 91 8106301 source
• Not checked yetcites [9] Yeargin-Allsopp M Rice C Karapurkar T Prevalence of autism in a US metropolitan area JAMA 2003 289 1 49 55 12503976 source
• Not checked yetcites [10] Banach R Thompson A Szatmari P Brief Report: Relationship between non-verbal IQ and gender in autism J Autism Dev Disord 2009 39 1 188 93 18594959 source
• Not checked yetcites [11] Fombonne E The epidemiology of autism: a review Psychol Med 1999 29 4 769 86 10473304 source

In the paper

“Males with ASD are found to show more externalizing behavior problems than females, such as aggressive behavior, hyperactivity, reduced prosocial behavior, and increased repetitive/restricted behaviors and interests [24*,25*,26**,27*,28].”

What the sources say

• Not checked yetcites [24*,25*,26**,27*,28]

In the paper

“studies of chromosomal structural variation that indicate that a higher proportion of female cases carry a de novo CNV than male cases and that these CNVs disrupt a greater number of genes than those from males [45,46*,47*].”

What the sources say

• Not checked yetcites [45,46*,47*]

In the paper

“In combination with the presence of a Y chromosome, this lack of paternal X expression could then raise ASD risk for both syndromes, and for a higher proportion of XYY cases as is observed.”

In the paper

“Baron-Cohen and colleagues have proposed that fetal testosterone (FT) levels may also drive cognitive hypermasculinization in ASD.”

In the paper

“ASD-diagnosed girls had a higher mean total problem score (hyperactivity, anxiety, and conduct, peer, and prosocial problems) and a higher frequency of low IQ than ASD-diagnosed boys.”

What the sources say

• Not checked yetcites [30**]

In the paper

“only the male-only linkage signal at 17q21 has been successfully replicated, and the exact risk genes or variants responsible for these linkage peaks remain unknown.”

What the sources say

• Not checked yetcites [35] Stone JL Merriman B Cantor RM Evidence for sex-specific risk alleles in autism spectrum disorder Am J Hum Genet 2004 75 6 1117 23 15467983 PMC1182147 source
• Not checked yetcites [36] Cantor RM Kono N Duvall JA Replication of autism linkage: fine-mapping peak at 17q21 Am J Hum Genet 2005 76 6 1050 6 15877280 PMC1196442 source
• Not checked yetcites [37] Szatmari P Paterson AD Zwaigenbaum L Mapping autism risk loci using genetic linkage and chromosomal rearrangements Nat Genet 2007 39 3 319 28 17322880 PMC4867008 source
• Not checked yetcites [38] Lamb JA Barnby G Bonora E Analysis of IMGSAC autism susceptibility loci: evidence for sex limited and parent of origin specific effects J Med Genet 2005 42 2 132 7 15689451 PMC1735992 source
• Not checked yetcites [39] Schellenberg GD Dawson G Sung YJ Evidence for multiple loci from a genome scan of autism kindreds Mol Psychiatry 2006 11 11 1049 60 16880825 source
• Not checked yetcites [40] Weiss LA Arking DE Daly MJ Chakravarti A A genome-wide linkage and association scan reveals novel loci for autism Nature 2009 461 7265 802 8 19812673 PMC2772655 source

In the paper

“The observed sex differences raise the possibility that male-typical externalizing behaviors are more disruptive in the home or school setting than female-typical internalizing behaviors, preferentially prompting evaluation and diagnosis for boys, especially as compared to high-functioning girls.”

In the paper

“In these studies, high-functioning ASD cases scored lower than typical males on measures of empathy and friendship, and higher than typical males on measures of systemizing.”

What the sources say

• Not checked yetcites [61] Baron-Cohen S Wheelwright S The empathy quotient: an investigation of adults with Asperger syndrome or high functioning autism, and normal sex differences J Autism Dev Disord 2004 34 2 163 75 15162935 source
• Not checked yetcites [62] Baron-Cohen S Wheelwright S The Friendship Questionnaire: an investigation of adults with Asperger syndrome or high-functioning autism, and normal sex differences J Autism Dev Disord 2003 33 5 509 17 14594330 source
• Not checked yetcites [63] Baron-Cohen S Richler J Bisarya D The systemizing quotient: an investigation of adults with Asperger syndrome or high-functioning autism, and normal sex differences Philos Trans R Soc Lond B Biol Sci 2003 358 1430 361 74 12639333 PMC1693117 source

In the paper

“Nevertheless, whether the male-skewed prevalence of ASD is due to biased diagnosis of sex-differential presentations of the disease or to true sex differences in prevalence (or both), sex-specific biology is likely to play a role.”

In the paper

“it appears that regardless of whether risk variants are inherited or de novo, in the face of a comparable degree of genetic liability, males are at increased risk for and females are protected from manifesting ASD symptoms that meet diagnostic criteria.”

In the paper

“levels of testosterone and its precursors were found to be significantly elevated in a sample of ASD cases, with 57 of the 70 subjects having at least one androgen metabolite measuring above the upper limit of sex- and age-matched reference ranges [69].”

What the sources say

• Not checked yetcites [69] Geier DA Geier MR A prospective assessment of androgen levels in patients with autistic spectrum disorders: biochemical underpinnings and suggested therapies Neuro Endocrinol Lett 2007 28 5 565 73 17984958

In the paper

“Recent work has even found a correlation between increasing FT and volume of sexually dimorphic brain regions, specifically increased volume of the right temporoparietal junction/posterior superior temporal sulcus and decreased volume of the planum temporale/parietal operculum and posterior lateral orbitofrontal cortex volume [68*].”

What the sources say

• Not checked yetcites [68*]

In the paper

“a study of rare copy number variants (CNVs) in ASD identified the first inherited autosomal variant with clear male-biased penetrance: males carrying a microdeletion in SHANK1 had high-functioning autism, while female relatives carrying the same microdeletion showed anxiety but did not meet diagnostic criteria for ASD [42**].”

What the sources say

• Not checked yetcites [42**]

In the paper

“other studies have failed to support the genetic loading hypothesis, including a study of 882 families [33] and another recent study of high risk siblings of autistic probands that found that only the sex of the sibling was a significant predictor of their future ASD status [34**].”

What the sources say

• Not checked yetcites [33] Goin-Kochel RP Abbacchi A Constantino JN Lack of evidence for increased genetic loading for autism among families of affected females: a replication from family history data in two large samples Autism 2007 11 3 279 86 17478580 source
• Not checked yetcites [34**]

In the paper

“One major theory that invokes a broad role for testosterone in ASD etiology is the Extreme Male Brain theory, which proposes that ASD arises from hypermasculinization of the brain [60].”

What the sources say

• Not checked yetcites [60] Baron-Cohen S The extreme male brain theory of autism Trends Cogn Sci 2002 6 6 248 254 12039606 source

In the paper

“these observations suggest several intriguing possibilities: 1) the Y chromosome is a risk factor for ASD, and 2) a second X chromosome is protective, possibly via genes that escape X-inactivation.”

In the paper

“genetic studies operating under this model hypothesize that females with ASD are likely to be carrying a higher heritable mutational “load” than affected males.”

What the sources say

• Not checked yetcites [31] Reich R Cloninger CR Guze SB The multifactorial model of disease transmission: I. Description of the model and its use in psychiatry Br J Psychiatry 1975 127 1 10 1139078 source

In the paper

“Girls without diagnoses showed increased communication difficulties, but reduced social impairments as compared to non-diagnosed boys.”

What the sources say

• Not checked yetcites [30**]

In the paper

“with an increased rate of ASD diagnosis in Turner syndrome (TS, XO, ~3% ASD) [52,53,54], Klinefelter syndrome (KS, XXY, ~10% ASD) [55,56*], and 47,XYY syndrome (~20% ASD), but no increased rate in X chromosome trisomy [57,58**].”

What the sources say

• Not checked yetcites [52] Donnelly SL Wolport CM Menold MM Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome Am J Med Genet 2000 96 3 312 6 10898907 source
• Not checked yetcites [53] Skuse DH James RS Bishop DV Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function Nature 1997 387 6634 705 8 9192895 source
• Not checked yetcites [54] Creswell C Skuse D Autism in association with Turner syndrome: Genetic implications for male vulnerability to pervasive developmental disorders Neurocase 1999 5 511 518 source
• Not checked yetcites [55,56*]
• Not checked yetcites [57,58**]

In the paper

“RORA regulates expression of aromatase, the enzyme that converts androgens to estrogens, and is reciprocally activated by estradiol and inhibited by testosterone [75*].”

What the sources say

• Not checked yetcites [75*]

In the paper

“3.84 M:F also reported for this clinical sample”

What the sources say

• Not checked yetcites [15] source

In the paper

“ASD cases documented in Taiwanese government registry found to be more prevalent in males (M:F near 6:1)”

What the sources say

• Not checked yetcites [16] source

In the paper

“The first population screening for ASD prevalence in children in South Korea.”

What the sources say

• Not checked yetcites [12] source

In the paper

“Large-scale prevalence estimates for co-morbidities in 14,000 ASD cases from retrospective examination of hospital records”

What the sources say

• Not checked yetcites [15] source

In the paper

“possibly due to the rigorous surveillance of ASD symptoms in this sample”

What the sources say

• Not checked yetcites [23] source

In the paper

“reporting an overall prevalence of 1 in 88 (1.1%), up from 1 in 110 in 2009”

What the sources say

• Not checked yetcites [13]

In the paper

“although a study of unaffected Japanese adults found no correlation between salivary testosterone levels and autistic-like traits [72].”

What the sources say

• Not checked yetcites [72] Takagishi H Takahashi T Yamagishi T Salivary testosterone levels and autism-spectrum quotient in adults Neuro Endocrinol Lett 2010 31 6 837 41 21196912

In the paper

“ASD risk is likely to be multifactorial, with many different genetic variants and environmental factors contributing to liability, and still other sex-differential genetic and hormonal factors acting to potentiate risk to males and/or attenuate risk to females (Figure 1B).”

In the paper

“These regulatory relationships may create a feedback loop that further elevates testosterone levels”

In the paper

“hypogonadism in XXY males in the face of a nearly 10-fold increase in ASD prevalence suggests that the role of the hormonal milieu in ASD liability is likely complex and may be mediated by other risk factors.”

In the paper

“Examination of the relationship between IQ, age, SES, sex, and race and autistic symptoms in 777 children, only IQ and age are found to have significant effects on ASD severity”

What the sources say

• Not checked yetcites [22] source

In the paper

“finding a higher-than-expected rate of ASDs overall (2.64%)”

What the sources say

• Not checked yetcites [12] source

In the paper

“The most recent report from the US CDC on ASD prevalence”

What the sources say

• Not checked yetcites [13]

In the paper

“supporting the multiple threshold model for ASD liability in which affected females have a higher genetic liability”

What the sources say

• Not checked yetcites [26] source

In the paper

“and M:F of 9:1”

What the sources say

• Not checked yetcites [18] source

In the paper

“Evidence suggests that sex chromosomal gene dosage and sex hormone levels may be involved in setting sex-specific liability thresholds”

In the paper

“identified a high proportion of autistic females in a general population (non-clinical) sample (M:F 2.5:1)”

What the sources say

• Not checked yetcites [12] source

In the paper

“and a low M:F of 2:1”

What the sources say

• Not checked yetcites [17] source

In the paper

“gonadal dysgenesis is common in TS and KS, causing abnormally low postnatal estrogen and testosterone levels, respectively, whereas testosterone levels are normal prenatally in KS and throughout life in 47,XYY cases [79,80].”

What the sources say

• Not checked yetcites [79] Price WH van der Molen HJ Plasma testosterone levels in males with the 47,XYY karyotype J Endocrinol 1970 47 1 117 22 5428907 source
• Not checked yetcites [80] Ratcliffe SG Read G Pan H Prenatal testosterone levels in XXY and XYY males Horm Res 1994 42 3 106 9 7995613 source

In the paper

“and in urban areas (urban:rural about 2.5:1)”

What the sources say

• Not checked yetcites [16] source

In the paper

“Population-based survey for ASDs among adults living in households (non-institutionalized) in England finds prevalence of 0.98%”

What the sources say

• Not checked yetcites [18] source

In the paper

“A recent, large, population-based twin study of ASD concordance”

What the sources say

• Not checked yetcites [32] source

In the paper

“Findings of ~60% concordance rate in monozygotic and ~25% concordance in dizygotic twin pairs”

What the sources say

• Not checked yetcites [32] source

In the paper

“Correlation of males’ fetal testosterone level with volume of brain regions found to be sexually dimorphic in size from a large data set of structural MRI images of brains from male and female children”

What the sources say

• Not checked yetcites [68] source

In the paper

“The first identified autosomal risk variant for ASD with clear male-specific penetrance”

What the sources say

• Not checked yetcites [42] source

In the paper

“with the highest rate (50% of 26 subjects) in 47,XYY cases”

What the sources say

• Not checked yetcites [58] source

In the paper

“Behavioral problems were also found to be more severe in the 47,XYY group”

What the sources say

• Not checked yetcites [58] source

In the paper

“finding several CNV events that recur independently in unrelated cases”

What the sources say

• Not checked yetcites [47] source

In the paper

“This study identifies rare, de novo CNVs in sporadic ASD cases”

What the sources say

• Not checked yetcites [47] source

In the paper

“finding a handful of genes that are recurrently hit by these rare variants”

What the sources say

• Not checked yetcites [48] source

In the paper

“supports a role for these rare variants in ASD risk”

What the sources say

• Not checked yetcites [46] source

In the paper

“and suggest that the gestational environment play a significant role in ASD susceptibility”

What the sources say

• Not checked yetcites [32] source

In the paper

“Finds a negative correlation between presentation of autistic traits and a measurement of cognitive flexibility in cases with Klinefelter syndrome”

What the sources say

• Not checked yetcites [56] source

In the paper

“and a potential association between these behaviors and performance on executive function tasks”

What the sources say

• Not checked yetcites [27] source

In the paper

“Identification of rare, de novo CNVs in sporadic autistic cases from nearly 1000 simplex families”

What the sources say

• Not checked yetcites [46] source

In the paper

“have recalibrated heritability estimates for ASD”

What the sources say

• Not checked yetcites [32] source

In the paper

“recurrence rate in siblings is 26.2% for males and 9.1% for females, regardless of the sex of their older autistic sibling”

What the sources say

• Not checked yetcites [34] source

In the paper

“Prospective study finds a recurrence risk of 18.7% for siblings of autistic probands”

What the sources say

• Not checked yetcites [34] source

In the paper

“males with a microdeletion in SHANK1 are autistic, while related female carriers are not affected with ASD”

What the sources say

• Not checked yetcites [42] source

In the paper

“Parental accounts report a greater degree of internalizing behaviors and depressive symptoms in females than males with ASDs”

What the sources say

• Not checked yetcites [29] source

In the paper

“and two ASD-associated co-expression modules that may represent expression changes caused by primary effects of genetic risk, and secondary effects of downstream pathophysiology”

What the sources say

• Not checked yetcites [76] source

In the paper

“transcription of RORA is activated by testosterone and inhibited by estrogen”

What the sources say

• Not checked yetcites [75] source

In the paper

“and RORA stimulates expression of aromatase”

What the sources say

• Not checked yetcites [75] source

In the paper

“Finding of integral role for RORA, a gene downregulated in ASD, in sex hormone metabolism”

What the sources say

• Not checked yetcites [75] source