why look for genes in ocd? - wordpress.com · 2016-03-17 · why look for genes in ocd? james j....
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Why look for genes in OCD? James J. Crowley, PhD Assistant Professor UNC Chapel Hill: Genetics & Psychiatry Karolinska Institutet: Clinical Neuroscience 16 March 2016 Hesselby Slott
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Outline 1. OCD is genetic 2. We will find OCD genes (I promise) 3. Finding genes could:
¤ inform diagnostic conceptualization ¤ reveal disorder mechanisms ¤ help patients
4. Specific aims
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OCD is genetic
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Family study
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Twin study
Helps dissect genetic vs environmental effects
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Correlations for self-reported Obsessive-Compulsive Symptoms among 16,383 twins aged 20 to 47 years in the STAGE study, stratified by zygosity and sex.
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Sullivan PF, Daly MJ, O'Donovan M. Genetic architectures of psychiatric disorders: the emerging picture and its implications. Nat Rev Genet. 2012, 13(8):537-51.
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Human trichotillomania gene in mice
Normal Sapap3 “knockout”
Welch JM et al. Cortico-striatal synaptic defects and OCD-like behaviors in Sapap3-mutant mice. Nature. 2007 23;448(7156):894-900.
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Canine compulsive disorder (CCD)
Tang R, et al. Candidate genes and functional noncoding variants identified in a canine model of OCD. Genome Biol. 2014, 14;15(3):R25.
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www.boredpanda.com/donald-trump-hair-look-alikes/
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Questions?
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We will find OCD genes
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DNA sources
Blood (white blood cells) Saliva (WBC & cheek cells)
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X X = error
http://justsomething.co/the-34-most-hilarious-pinterest-fails-ever/
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DNA variation
¨ Human genome is ~3 billion letters ¨ Variation:
¤ Single nucleotide polymorphism (SNP, ~3 million/person):
¤ Copy number variant (CNV, ~10,000/person):
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DNA genotyping
¤ a collection of microscopic DNA spots (“probes”) attached to solid surface
¤ for each SNP, two “probes” present ¤ ~1 million SNPs/microarray
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Inheritance – complex traits
Few “tall” gene variants
Many “tall” gene variants
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Association
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Genome-wide association study (GWAS)
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Genome-wide association study (GWAS)
“Manhattan plot”
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Genome-wide association study (GWAS)
“Manhattan plot”
Street
Hei
ght
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q
Cases: 2,601 Controls: 3,345 Hits: 0
Schizophrenia GWAS: 2009
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“Omaha plot”
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Cases: 9,394 Controls: 12,462 Hits: 5
Schizophrenia GWAS: 2011
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q
Cases: 27,785 Controls: 28,441 Hits: 62
Nature Genetics 45, 1150-1159 (2013)
Schizophrenia GWAS: 2012
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Cases: 35,476 Controls: 46,839 Hits: 108
Biological insights from 108 schizophrenia-associated loci. Nature 511, 421-427 (2014)
Schizophrenia GWAS: 2014
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DRD2
Dopamine (current pharmacotherapy)
Schizophrenia GWAS: 2014
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¨ Large, well-phenotyped samples key! ¨ Many genes involved ¨ Even genes of small effect can be important:
¤ Schizophrenia: DRD2 variant increase risk just 10%, yet all antipsychotics bind to this receptor
¤ Cholesterol: HMGCR variant increases cholesterol just 5%, yet statins (best selling drug in the world) inhibit this enzyme
Psychiatric GWAS: lessons learned
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Questions?
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Finding genes could…
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Inform diagnostic conceptualization
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Reveal disorder mechanisms
http://www.nytimes.com/2016/01/28/health/schizophrenia-cause-synaptic-pruning-brain-psychiatry.html
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Help patients
¨ identify at-risk individuals ¨ promote earlier intervention ¨ help with differential diagnosis ¨ help guide treatment choices ¨ lead to rational drug development
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Specific aims
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Funded by VR
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Pending @ NIH
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THANKS!