Overview of MRC Centre for Neuropsychiatric Genetics and Genomics

Michael J Owen

MissionUse genetics and genomics to inform our understanding of the aetiology, pathogenesis and classification of the major psychiatric and neurodegenerative disorders.

Train a cadre of clinical and non-clinical scientists capable of delivering this discovery and translational agenda.

Genetics

Clinical Studies

Pre-clinicalStudies

PopulationStudies

Major disease fociThe major causes of psychiatric

morbidity and mortality including:– Neurodegenerative disorders

• Alzheimer disease• Parkinson disease• Huntington disease

– Schizophrenia– Mood disorder

• Bipolar Disorder• Unipolar Disorder

– Childhood psychiatric and developmental disorders

• ADHD• Depression• Dyslexia

Cross cutting themes

• Psychosis and Major Affective Disorders.– Nick Craddock

• Neurodegenerative Disorders.– Julie Williams

• Developmental Disorders.– Anita Thapar

• Genetic and Cellular models.– Lawrence Wilkinson

• Biostatistics and Bioinformatics.– Peter Holmans

2010 Cardiff University establishes 3 cross school research institutes.

NMHRI MissionHarness the internationally recognised strengths in neuroscience research in Cardiff to deliver new insights into the major neurodegenerative and psychiatric disorders.

Major focus on developing novel translational interfaces between the work of MRC Centre for Neuropsychiatric Genetics and Genomics and the wider Cardiff Neurosciences community.

The Gateway Building

MRC centre support for biostatistics and bioinformatics

• Databasing and biostatistics posts.• SL in bioinformatics/ computational biology.• 3 joint PhD students with COMSC.• Regular forum

– to encourage joint research.

• Existing collaboration on MSc.

What we do• Genomic data

– Genome-wide association studies– Genome-wide copy number variation– Whole exome and genome sequencing

• Other data– Transcriptomics– Proteomics– Annotated complexes and pathways– Brain imaging– Cognition– Clinical including routinely collected data

• Very complex genetics• We seek insights into:

– Association of single and multiple DNA events with other datasets– Nature of interactions– Disease pathways and other biological relationships

BD: modulation of transcription and cellular activity, including via hormonal action

12

Copy Number Variants

deletion

duplication

Comparative Genomic Hybridisation

SNP Chips

Do SZ CNVs converge on synaptic pathways?

• Causal role of most individual CNVs not established

• Annotation gap• Biases esp gene size not

excluded in most studies• One study using formal test

found nominal evidence for enrichment in “neuronal-activity” and “learning gene” sets in ISC vs controls (Raychaudhuri et al 2010).

• Study of de novos

Challenges

• Extracting biological meaning from multiple genetic signals

• Algorithms and platforms for estimating disease risk• Prediction of functional consequences of sequence

variation• Understanding relationships between complex

genomic data and complex phenotype data (clinical, cognitive, imaging etc)

• Linking research and routinely collected clinical data