Background. We anticipate that a collection of rare variants will be found to be associated with major neuropsychiatric disease over the course of sequencing projects over the next year. The Daly lab is responsible for some of those efforts, particularly in relation to a large sample of autism spectrum disorder cases. While associating new genetic variants with mental illness will add much to existing etiologic awareness, many of the questions that follow other forms of genetic association will equally apply to whole genome sequencing. As with strongly predisposing copy number variants, newly discovered rare variants are likely to have highly pleiotropic effects, the nature of which his largely obscured in case-control studies.

Aims. We hope to examine the average quantitative effect of rare variants (both copy number variants and single nucleotide variants) in coding regions associated with major neuropsychiatric disease on trait measures of behavior and cognition in the ALSPAC/UK10K data. The specific aims of the study are as follows:

To examine the range of behaviors and average impairment burden associated with autism,

schizophrenia, and bipolar disorder-implicated rare variants using the following outcome

measures: IQ, autism-like social and communication impairment, psychotic traits, overall behavior

difficulties, and language ability.

Hypotheses. The predictor set will include rare variants in the ALSPAC/UK10K data that fall in the same genes as those found to harbor rare variation associated with autism, schizophrenia, and bipolar disorder. We hypothesize that, en masse, those variants will predict a shift towards affectedness in distributions of behavioral and cognitive impairment in the ALSPAC/UK10K cohort.

Exposure variables- Genotypic variation in the UK10K sequencing data

Outcome variables-

IQ (Full, Verbal, Nonverbal) - Ages 8 (WISC) and 15 (WASI)

Behavior Problems (Strengths and Difficulties Questionnaire) - All available time points

Autistic Traits (Social and Communication Disorders Checklist) - All available time points

Psychotic Traits (PLIKS) - All available time points

Language Ability (Children's Communication Checklist) - All available time points

Control/ Additional Variables-

Sex of the Child

Parental Age (Maternal and Paternal)

Child's Ethnicity

Maternal Education

Child's Age

Child's Height (phenotypic specificity consideration)

Child's Weight (phenotypic specificity consideration).