Chun Chieh Fan

Bio: Chun Chieh Fan is an academic researcher from University of California, San Diego. The author has contributed to research in topics: Genome-wide association study & Medicine. The author has an hindex of 30, co-authored 131 publications receiving 4144 citations. Previous affiliations of Chun Chieh Fan include Lundbeck & University of California, Berkeley.

Genome-wide association study identifies 30 loci associated with bipolar disorder

Abstract: Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

The genetic architecture of the human cerebral cortex

Abstract: The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.

Exploring Comorbidity Within Mental Disorders Among a Danish National Population.

Abstract: Importance: Individuals with mental disorders often develop comorbidity over time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity. Objectives: To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age- and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice. Design, Setting, and Participants: This population-based cohort study included all individuals born in Denmark between January 1, 1900, and December 31, 2015, and living in the country between January 1, 2000, and December 31, 2016. The analyses were conducted between June 2017 and May 2018. Main Outcomes and Measures: Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, 10th Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% CIs were calculated using Cox proportional hazards regression models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated. Results: A total of 5940778 persons were included in this study (2958293 men and 2982485 women; mean [SD] age at beginning of follow-up, 32.1 [25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% CI, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years). Conclusions and Relevance: Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility..

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

Abstract: Personality is influenced by genetic and environmental factors and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132-260,861). Of these genome-wide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422-18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit-hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion-introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety).

Human biochemical genetics

Abstract: So far in this course we have dealt entirely with the evolution of characters that are controlled by simple Mendelian inheritance at a single locus. There are notes on the course website about gametic disequilibrium and how allele frequencies change at two loci simultaneously, but we didn’t discuss them. In every example we’ve considered we’ve imagined that we could understand something about evolution by examining the evolution of a single gene. That’s the domain of classical population genetics. For the next few weeks we’re going to be exploring a field that’s actually older than classical population genetics, although the approach we’ll be taking to it involves the use of population genetic machinery. If you know a little about the history of evolutionary biology, you may know that after the rediscovery of Mendel’s work in 1900 there was a heated debate between the “biometricians” (e.g., Galton and Pearson) and the “Mendelians” (e.g., de Vries, Correns, Bateson, and Morgan). Biometricians asserted that the really important variation in evolution didn’t follow Mendelian rules. Height, weight, skin color, and similar traits seemed to

Integrative analysis of 111 reference human epigenomes

Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019.

Abstract: The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 × 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ∼90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high-throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/.

Clinical Diagnosis of Alzheimer's Disease

Abstract: There are a number of ways in which a clinical diagnosis of dementia of the Alzheimer type can be made – the application of clinical criteria is the commonest but ancillary techniques such as neuroima