NIMH (National Institute of Mental Health) De Novo Mutation Identification in Taiwanese Schizophrenia Trios

The substantial reproductive impact of schizophrenia, for which affected individuals have fewer than half as many offspring as unaffected individuals do, implies that mutations of largest effect will frequently be de novo mutations. Ascertaining exome sequence variation in father-mother-offspring trios allows such mutations to be identified and distinguished from the far-larger amount of rare variation that is inherited by each individual. The pursuit of this approach in a large, well-powered cohort of trios can also provide lessons that inform the development of such gene discovery strategies more generally in human genetics.

Schizophrenia trios from the Taiwanese population are being collected by Dr. Ming Tsuang (PI, UC San Diego, California) and investigators in Taiwan (PI, Dr. Hai Gwo Hwu; both funded by NIMH grant 1R01MH085560; Expanding Rapid Ascertainment Networks of Schizophrenia Families in Taiwan). A total of 3800 trios are anticipated to be collected by May 2013. This represents a highly homogenous national sample from the same ancestral population.

DNA samples will be obtained from the NIMH Repository, Rutgers University Cell and DNA Repository (described below) and stored at the Broad Institute. Genetic and data analyses will be performed at the Broad Institute. We propose to sequence the whole exome of trios by hybrid capture and Illumina next generation sequencing and perform targeted genotyping and validation of variants (SNPs, indels and CNVs) using several molecular methods, to include emulsion-based PCR and Sanger sequencing.

• Study Design:
  • Case-Control
• Study Type:
  • Case-Control
  • Parent-Offspring Trios
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 5196
• Subject Sample Telemetry Report (SSTR)

• BioProject
• PubMed
• Sequence Read Archive
• BioSample
• MeSH
• PMC

Inclusion:

• Family trios from Taiwan
• Family must have undergone full diagnostic evaluation using NIMHs Diagnostic Interview for Genetic Studies (DIGS)
• Assessment of other medical conditions
• All probands met Diagnostic and Statistics Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia
• Collection of associated blood samples from parents and in some cases siblings, if applicable

Exclusion:

• N/A

Schizophrenia trios from the Taiwanese population were collected by Dr. Ming Tsuang (PI, UC San Diego, California) and investigators in Taiwan (PI, Dr. Hai Gwo Hwu; both funded by NIMH grant 1R01MH085560; Expanding Rapid Ascertainment Networks of Schizophrenia Families in Taiwan). Samples were collected from a total of 5260 participants and 5085 of these were sequenced.

All schizophrenia probands were ascertained from psychiatric hospitals throughout the entire island of Taiwan, and underwent a full diagnostic evaluation using the NIMHs Diagnostic Interview for Genetic Studies (DIGS) which provides advanced characterization of schizophrenia symptoms as well as those of most other major classes of psychiatric and substance use disorders, and a survey of other medical conditions as well. Each record contains admission and discharge dates, main discharge diagnosis and secondary diagnoses. All probands met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia. Blood samples were collected from parents and in some cases, siblings. Blood samples collected from study participants are sent to the National Institute of Mental Health (NIMH) Center for Collaborative Studies of Mental Disorders at the Rutgers University Cell and DNA Repository (RUCDR) for DNA extraction and storage. Mental health information, including diagnosis, will be utilized for data analyses.

DNA samples were obtained from the NIMH Repository, Rutgers University Cell and DNA Repository (described below) and stored at the Broad Institute. Genetic and data analyses were performed at the Broad Institute. The whole exome of trios was sequenced by hybrid capture and Illumina next generation sequencing, Target genotyping was performed as well as validation of variants (SNPs, indels and CNVs) using several molecular methods, to include emulsion-based PCR and Sanger sequencing.

• Primary Phenotype: Schizophrenia
• Control Groups
• Parents

• Principal Investigator
  • Steven McCarroll. The Broad Institute of Harvard and MIT, MA, USA.
• Co-Investigator
  • Giulio Genovese. The Broad Institute of Harvard and MIT, MA, USA.
• Funding Source
  • NIMH Grant 1R01MH085560. National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA.
• External PI/Collaborator
  • Ming Tsuang. National Taiwan University, Taipei, Taiwan.
  • NHai Gwo Hwu. National Taiwan University, Taipei, Taiwan.