Pleiotropic Mechanisms Indicated for Sex Differences in Autism

Sexual dimorphism in common disease is pervasive, including a dramatic male preponderance in autism spectrum disorders (ASDs). Potential genetic explanations include a liability threshold model requiring increased polymorphism risk in females, sex-limited X-chromosome contribution, gene-environment interaction driven by differences in hormonal milieu, risk influenced by genes sex-differentially expressed in early brain development, or contribution from general mechanisms of sexual dimorphism shared with secondary sex characteristics. Utilizing a large single nucleotide polymorphism (SNP) dataset, we identify distinct sex-specific genome-wide significant loci. We investigate genetic hypotheses and find no evidence for increased genetic risk load in females, but evidence for sex heterogeneity on the X chromosome, and contribution of sex-heterogeneous SNPs for anthropometric traits to ASD risk. Thus, our results support pleiotropy between secondary sex characteristic determination and ASDs, providing a biological basis for sex differences in ASDs and implicating non brain-limited mechanisms.


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Tummy Troubles (TT) [8,9]: To confirm ASD diagnoses, children (5-18 years old) in the ASD group were 17 assessed with the ADOS. Exclusion criteria included severe sensory or motor impairment, 18 neurodevelopmental disorders of known etiology (e.g. Fragile X Syndrome), gestational age less than 36 19 or greater than 42 weeks, and birth weight less than 2,500 grams. These individuals were also recruited 20 on the basis of positive/negative GI symptoms as described [8]. adults (individuals aged 18 years or older) must have consented for themselves or been consented by a 1 legally authorized representative, children must be aged 4 years or older and under age 18 years. SCQ-2 lifetime questionnaires were used to support reported ASD diagnoses (SCQ score at least 12). IAN 3 reported diagnoses were previously validated[10].

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Childhood Autism Risks from Genetics and the Environment (CHARGE) [11]: Eligibility is ages 2 to 5 5 years at enrollment, born in California, living with biological mother, parent and child speak English or 6 Spanish, current residence in a 22 county region of California. Exclusions: children with such severe 7 disabilities such that standardized instruments would provide invalid measures, e.g. blindness. All 8 children who were recruited with a previous diagnosis of autism or an ASD were evaluated using 9 ADOS[4] and Autism Diagnostic Interview, Revised (ADI-R) [12]. Only confirmed cases, based on 10 standard criteria were classified as ASD [13]. All control children who were recruited from the general 11 population or from a group with developmental delays other than an ASD were administered the MSEL[6],

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General population controls whose scores were higher than two standard deviations (SD) below the 14 mean on one and higher than 1.5 SD below mean on the other, and <12 on the SCQ were classified as 15 typically developed controls. Any child who scored >12 on the SCQ was further evaluated using the 16 ADOS and ADI-R. If they met criteria for an ASD, they were classified as ASD. All tests were 17 administered by trained clinicians who had attained research reliability on the instruments they

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Lifetime Edition) ruled out ASD risk and the MSEL[6] revealed developmental scores 2 SD of the mean 3 3 for performance quotient and verbal quotient subscales. Exclusion criteria for controls included a 1 diagnosis of specific language impairment, or any known developmental, neurological, or behavioral 2 problems. Further inclusion criteria for all children, both controls and children with ASDs, included being 3 native English speakers, ambulatory, and with no suspected vision or hearing problems. All diagnostic 4 assessments were conducted or directly observed by trained, licensed clinical psychologists who 5 specialize in ASD and had been trained according to research standards for these tools. contact, having a caregiver who could communicate in English (or Spanish at two sites), and within the 10 age range for validated study instruments were eligible. Access to birth certificates and legal consent 11 were required. ASD ascertainment was through a broad array of sources serving or evaluating children 12 with developmental problems or by direct parent contact to the study. Individuals with an ASD or related 13 diagnosis (e.g. intellectual disability, developmental delay) or early intervention or special education

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When for a single cohort more then one IQ scale assessment is available, we considered IQ scale 3 assessments that allowed the inclusion in the analysis of the largest sample size. We assigned each 4 individual with available IQ data to low IQ category (IQ < 70) or high IQ category (IQ > 80) based on 5 criteria already set by the AGP cohort using verbal, non-verbal (performance) and full-scale IQ