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Title: The genetics of autism and related traits
Author: Warrier, Varun
ISNI:       0000 0004 7229 7771
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Autism Spectrum Conditions (henceforth, autism) refers to a group of neurodevelopmental conditions characterized by difficulties in social interaction and communication, difficulties in adjusting to unexpected change, alongside unusually narrow interests and repetitive behaviour, and sensory hyper-sensitivity. Twin and family-based studies have consistently identified high heritabilities for autism and autistic traits, with recent studies converging at 60 – 90% heritability. Common genetic variants are thought to additively contribute to as much as 50% of the total risk for autism. In this thesis, I investigate the contribution of common genetics variants (including SNPs, and InDels) to autism and related traits. In Chapter 1, I discuss the recent advances in the field of autism genetics, focussing on the contribution of common genetic variants to the risk for autism. Chapters 2 – 7 report the results of various studies investigating the genetic correlates of autism and related traits. In Chapter 2, I surveyed the evidence for 552 candidate genes associated with autism, and conducted a meta-analysis for 58 common variants in 27 genes, investigated in at least 3 independent cohorts. Meta-analysis did not identify any SNPs that were replicably associated with autism in the Psychiatric Genetics Consortium genome-wide association study (PGC-GWAS) dataset after Bonferroni correction, suggesting that candidate gene association studies are not statistically well-powered. In Chapters 3 – 7, I conducted genome-wide association studies (GWAS) for 6 traits associated with autism: self-reported empathy (N = 46,861, Chapter 3), cognitive empathy (N = 89,553, Chapter 4), theory of mind in adolescents (N = 4,577, Chapter 5), friendship satisfaction (Neffective = 158,116) and family relationship satisfaction (Neffective = 164,112, both Chapter 6), and systemizing (N = 51,564, Chapter 7). GWAS identified significant loci for self-reported empathy, systemizing, friendship and family relationship satisfaction, and cognitive empathy. Genetic correlation analyses replicably identified a significant negative genetic correlation between autism and family relationship satisfaction and friendship satisfaction, and a significant positive genetic correlation between autism and systemizing. In addition, there was a negative genetic correlation between autism and self-reported empathy. Chapter 8 draws all of these studies together, concluding that there may be at least two independent sources of genetic risk for autism: one stemming from social traits and another from non-social traits. I discuss some future directions about how this can be leveraged using polygenic scores from multiple phenotypes to potentially stratify individuals within the autism spectrum, and both the strengths and limitations of the reported studies.
Supervisor: Baron-Cohen, Simon Sponsor: University of Cambridge
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Autism ; genetics ; genome-wide association studies