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Discovering genes involved in disease and the mystery of missing heritability

UCLA Previously Published Works (2015)

Many challenges related to understanding the mystery of missing heritability and discovering the variants involved in human disease require analysis of large datasets that present opportunities for computer scientists. majority of these discoveries were made using a type of genetic study called a genome-wide association study (GWAS). In a GWAS, data from a large number of individuals is collected, including both a measurement of the disease-related trait as well as information on genetic variants from the individual. The field of genetics assumes a standard mathematical model for the relationship between genetic variation and traits or phenotypes. This model is called the polygenic model. An insight into missing heritability emerged from what initially seemed like an unrelated development addressing an orthogonal problem in association studies. GWAS statistics make the same assumptions as linear regression, which assumes the phenotype of each individual is independently distributed. The basis of the mixed model approach to population structure is the insight the proportion of the genome shared corresponds to the expected similarity in the values of the unmodeled factors. The developments in mixed models provide interesting opportunities for phenotype prediction, which is a problem with a rich history in genetics, particularly in the literature on the best linear unbiased predictor (BLUP).

Cover page: Discovering genes involved in disease and the mystery of missing heritability

Article
Peer Reviewed

Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples

UC San Diego Previously Published Works (2006)

The dopamine transporter (DAT) is the site of action of stimulants, and variations in the human DAT gene (DAT1) have been associated with susceptibility to several psychiatric disorders including attention deficit hyperactivity disorder (ADHD) and bipolar disorder. We have previously reported the association of bipolar disorder to novel SNPs in the 3' end of DAT1. We now report the identification of 20 additional SNPs in DAT1 for a total of 63 variants. We also report evidence for association to bipolar disorder in a second independent sample of families. Eight newly identified SNPs and 14 previously identified SNPs were analyzed in two independent samples of 50 and 70 families each using the transmission disequilibrium test. Two of the eight new SNPs, one in intron 8 and one in intron 13, were found to be moderately associated with bipolar disorder, each in one of the two independent samples. Analysis of haplotypes comprised of all 22 SNPs in sliding windows of five adjacent SNPs revealed an association to the region near introns 7 and 8 in both samples (empirical P-values 0.002 and 0.001, respectively, for the same window). The haplotype block structure observed in the gene in our previous study was confirmed in this sample with greater resolution allowing for discrimination of a third haplotype block in the middle of the gene. Together, these data are consistent with the presence of multiple variants in DAT1 that convey susceptibility to bipolar disorder.

Cover page: Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples

Article
Peer Reviewed

Gene networks associated with conditional fear in mice identified using a systems genetics approach

UCLA Previously Published Works (2011)

Background: Our understanding of the genetic basis of learning and memory remains shrouded in mystery. To explore the genetic networks governing the biology of conditional fear, we used a systems genetics approach to analyze a hybrid mouse diversity panel (HMDP) with high mapping resolution.Results: A total of 27 behavioral quantitative trait loci were mapped with a false discovery rate of 5%. By integrating fear phenotypes, transcript profiling data from hippocampus and striatum and also genotype information, two gene co-expression networks correlated with context-dependent immobility were identified. We prioritized the key markers and genes in these pathways using intramodular connectivity measures and structural equation modeling. Highly connected genes in the context fear modules included Psmd6, Ube2a and Usp33, suggesting an important role for ubiquitination in learning and memory. In addition, we surveyed the architecture of brain transcript regulation and demonstrated preservation of gene co-expression modules in hippocampus and striatum, while also highlighting important differences. Rps15a, Kif3a, Stard7, 6330503K22RIK, and Plvap were among the individual genes whose transcript abundance were strongly associated with fear phenotypes.Conclusion: Application of our multi-faceted mapping strategy permits an increasingly detailed characterization of the genetic networks underlying behavior. © 2011 Park et al; licensee BioMed Central Ltd.

Cover page: Gene networks associated with conditional fear in mice identified using a systems genetics approach

Article
Peer Reviewed

Genome-wide association study of Tourette's syndrome.

UCLA Previously Published Works (2013)

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Cover page: Genome-wide association study of Tourette's syndrome.