Dissertation
Genetic signatures of neurodevelopment and language: a thesis in two parts
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2021
DOI: 10.17077/etd.005887
Abstract
This thesis represents a diverse set of research projects investigating the genetic basis of human traits ranging from language ability, to neurodevelopment (autism), to creativity. Fundamentally, each of these topics reveal some aspect of the biology which defines and distinguishes human beings from our closest relatives. Practically, this work is unified by burgeoning attempts to rectify common and rare genetic variants while moving beyond monogenic paradigms.
Part one of this thesis involves two studies of autism. The first is a genetic case study of twin boys with autism and severe apraxia of speech, but very little sensory sensitivity and generally high sociability. Utilizing whole genome sequencing of the parents and probands, no de novo variants in known autism genes were found. A preponderance of polygenic common and rare variant risk was observed in the probands, however, which was inherited primarily from the mother. The second study represents the first large-scale survey in autism for symptoms of Avoidant Restrictive Food Intake Disorder (ARFID), an under-diagnosed eating disorder which overlaps with common eating issues in autism (e.g. extreme pickiness). This study estimated that up to 22% of autistic children are at risk for ARFID, and an empirical power analysis estimated 10,000 subjects are needed to perform a reasonable genome wide association study on the trait.
Part two focuses on language ability, including a review of the known overlap between putative language genes and neuropsychiatric risk genes. This review emphasizes genetic associations which are also supported by molecular or imaging-based studies and proposes that interrogation of language in neuropsychiatric studies can promote a more nuanced understanding of the biology underlying these conditions. Also described here is the first ever whole genome sequencing study of a cohort thoroughly phenotyped for language ability.
This study leveraged polygenic risk scores for neuropsychiatric and cognitive traits to highlight the intersections and distinctions between IQ and language ability. This analysis found a strong association of polygenic score for educational attainment with IQ and vocabulary --- while polygenic cognitive performance had stronger associations with verbal memory and receptive language skills --- suggesting the shared basis of language and IQ manifests in long-term traits, rather than moment-to-moment cognition. The study also found support for the putative language gene NDST4, based on a Sequence Kernel Association Test (SKAT) for the combined effects of common and rare variation. Finally, the study utilized machine learning to aggregate ultra-rare variation, which identified widespread neurodevelopmental signatures associated with verbal memory and evolutionary signatures including an over-representation of reversions to ancestral allele.
The appendices include descriptions of several unpublished works. This includes the development of a pilot set of web-based screening tools for language ability in adults. Traditional method of language assessment are typically labor and time intensive, so these assessments focus on collecting rich data --- including audio recordings --- which can be automatically scored or annotated. The last study described involves a survey of over 2,000 individuals capturing creative and media consumption habits, as well as self-report and family history of neuropsychiatric conditions. Distinct patterns of creative behavior were identified through hierarchical clustering, and the rates of neuropsychiatric conditions were differentially distributed across these profiles. For example: individuals in the cluster most enriched for interest in reading and writing were 1.5 times as likely to have bipolar disorder, while those in a cluster with high interest in visual art --- but not music --- were enriched for ADHD and major depression. This work adds to an existing body of literature suggesting that creativity may be supported by cognitive processes that also underlie neuropsychiatric risk.
Details
- Title: Subtitle
- Genetic signatures of neurodevelopment and language: a thesis in two parts
- Creators
- Tanner Koomar
- Contributors
- Jacob Michaelson (Advisor)Alexander Bassuk (Committee Member)Benjamin Darbro (Committee Member)Andrew Kitchen (Committee Member)Joshua Weiner (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Summer 2021
- DOI
- 10.17077/etd.005887
- Publisher
- University of Iowa
- Number of pages
- xvi, 183 pages
- Copyright
- Copyright 2021 Tanner Koomar
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 145-183).
- Public Abstract (ETD)
The work presented here is fundamentally concerned with the question; how does the human mind produce the complex behaviors which separate us from all other animals? This topic is approached though several distinct — but ultimately interconnected — lenses: language ability, creativity, and neurodevelopment (autism). The primary tool employed in these investigations is genetics, the fundamental building block of all life on earth.
In particular, this work promotes an increased understanding of the interplay between genetic changes present in many people, and those which are much rarer. In a case study of a set of twins with autism, combining these types of changes across the entire genome was much more informative than traditional investigation of individual genes. This sort of aggregation also revealed that changes to the few DNA differences between humans and chimpanzees have an outsized impact on language ability.
The studies that follow also highlight the overlap and shared roots of these traits. Survey results from over 2,000 people revealed that certain patterns of creativity and media consumption were particularly associated with neuropsychiatric conditions. Conversely, a group of respondents who described themselves as "less creative" reported fewer neuropsychiatric diagnoses in themselves and their immediate family. This speaks to a growing appreciation that no element of the human mind exists in a vacuum, and that these intersections are biologically relevant and observable down to the level of genes.
- Academic Unit
- Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984124268302771
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