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Genetics of Bipolar Disorders WADE BERRETTINI, MD, PhD Karl E. Rickels Professor and Director, Center for Neurobiology and Behavior, University of Pennsylvania [email protected], 215-8980092 William Styron (author): “Mysteriously, and in ways that are totally remote from natural experience, the gray drizzle of horror induced by depression takes on the quality of physical pain… The pain is unrelenting, and what makes the condition intolerable is the foreknowledge that no remedy will come---not in a day, an hour, a month or a minute. It is hopelessness even more than pain that crushes the soul…One does not abandon, even briefly, one’s bed of nails, but is attached to it wherever one travels." Theodore Roethke (poet): “For no reason I started to feel very good. My mind raced. I didn’t sleep much. Suddenly I knew how to enter into the life of everything around me. It was a wonderful feeling. I passed a diner and all of a sudden I knew what it felt like to be a lion. I went into the diner and said to the counterman, “Bring me a steak. Don’t cook it. Just bring it.” So he brought me this raw steak and I started eating it.” Principles for Psychiatric Genetics Current categorization of psychiatric illnesses defines separate syndromes (eg, bipolar disorder and schizophrenia) as distinct, non-overlapping entities, despite the fact that they share clinical characteristics and genetic liability. Genetic risk for psychiatric disorders is polygenic, meaning that hundreds to thousands of DNA variants (alleles) from hundreds of genes may contribute risk alleles for a given category of illness. Each common allele will have a small effect on risk. Rare alleles may have large effects on risk. Both rare and common variants will explain fractions of the genetic liability for psychiatric disorders. Rare variants may have substantial effects on risk. BPD & SZ Share Characteristics CHARACTERISTIC Onset in young adulthood Men & women at equal risk Occur at ~1% across the world Higher risk for suicide Chronic, episodic course Hallucinations and/or delusions Cognitive deficits Increased risk for drug addiction Treated by atypical antipsychotics Elevated risk for MDD in relatives Heritability estimate of ~80% BPD ++ ++ + ++ ++ + + + + + + SZ ++ ++ + + + ++ ++ + ++ + + Disrupted in SZ 1 (DISC1) ♦ A large kindred segregating multiple psychiatric phenotypes has a translocation (1;11)(q42;q14.3) which was present in many affecteds but generally not in well relatives (Blackwood et al, AJHG 2001). ♦ The translocation breakpoint disrupts a gene, DISC1 and was also associated with a decreased amplitude and delayed latency of an EEG-detectable event potential, the P300. DISC1 in SZ: the pedigree RUP RUP 10 RUP cases 1 BP case 7 SZ cases BP SZ Copy Number Variations (CNVs) in SZ Genome-wide association studies of SZ have been used to detect CNVs, and several are found at 10-fold (or higher) increased frequency in cases. These CNVs are rare & have limited penetrance. (Vassos et al, Hum Mol Genet, 2010) The human genome includes ~ 3 billion base pairs of DNA, in 23 pairs of chromosomes. A gene is a DNA sequence which encodes a protein. A typical gene is 20,000 base pairs in length. An allele is a variation in DNA sequence. The most common DNA variation in the genome is the single nucleotide polymorphism (SNP). There are 3,000,000 common SNPs in the human genome. Allele 1 Allele 2 CTAGTC CTATTC GATCAG GATAAG In the SNP example above, the 4th base pair is G:C or T:A The functional importance of most SNPs is unknown. ADVANCES in DNA TECHNOLOGY ~1,000,000 SNP CHIPs provide the ability to obtain a genotype at 1 SNP every ~ 3000 base pairs in the genome, allowing determination of most common SNPs. Allele-specific fluorescently-tagged DNA fragments (known as oligonucleotides) are mounted on the slide. The oligonucleotides are sequence-specific for one of the two alleles of a given SNP. The fluorescent tag will emit energy at a specific wavelength (color), only in the presence of the specific SNP allele for which they have been designed. If this genotyping is done for 1000’s of cases and 1000’s of controls, at every common SNP it can be determined whether an allele is more common among cases than controls. CACNA1c 0 1 2 3 4 5 6 7 8 -log10(pvalue) 9 10 BPD Genome-Wide Association Results 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 10 20 22 Chromosomes 15 17 19 21 CACNA1C: A BPD Risk Gene w An L-type calcium channel gene, alpha 1C subtype w Mutations in CACNA1C cause Timothy Syndrome, including autistic features and abnormal heartbeats. w The CACNA1C gene produces a protein which binds lamotrigine (Lamictal) a medication approved to treat bipolar disorder. Nature , 2014 ♦ GWAS of 36,000 cases and 105,000 controls. MHC locus 108 genomic regions implicated in Genetic risk for SZ. Many of these Have biologic support (eg, studies in post mortem SZ brain reveal abnormalities in mRNA and/or protein. Mir 137 CACNA1c Genomic sequencing results for 5303 MDD cases and 5337 controls of Chinese ethnicity (Nature, 2015). When analysis was restricted to melancholia cases (4509), significance increased by 2 orders of magnitude at the SIRT1 locus to 10-10 SIRT 1 LHPP LHPP: phospholysine phosphohistidine inorganic pyrophosphate phosphatase ♦ Very little known! ♦ SIRT1: Sirtuin 1 ♦ an evolutionarily conserved NAD(+)dependent histone deacetylase that is necessary for caloric restriction-related lifespan extension. SIRT1, as an intracellular energy sensor, detects the concentration of intracellular NAD(+) and uses this information to adapt cellular energy output to cellular energy requirements Nature Genetics, 45:984, 2013 1. GWAS data for SZ, BPD, RUP, autism & ADHD were compared to determine whether alleles nominally significant (!) in one illness were also nominally significant in any other disorder. 2. But, each of these GWAS reports contains > 106 alleles, so 5% (50,000) of these alleles are nominally significant in each GWAS randomly (they are false positives). 3. There is no method to determine which are true positives. Shared Alleles Across Multiple Diagnostic Entities *Consistent with family studies ^Inconsistent with family studies ^ * * * * ^ ^ ^ Reasons to Use Lithium Prophylaxis in BPD Blood levels are a check on compliance. Good tolerability Specific effect to reduce suicide. Less adverse metabolic effects than many other FDA-‐approved treatments. • Efficacy established through 50 years of study. • • • • Lithium PGX in Bipolar Disorder (Mertens et al, Nature, 2015) BPI pa@ents on lithium as the sole psychotropic were followed every 3 months to ensure euthymia for 2 years. Those who remained well were termed lithium responsive (LR). Pa@ents who relapsed to mania or depression were deemed lithium NR. Skin biopsies were taken to create iPSC-‐derived cultured neurons. Neurons from BPI pa@ents were hyperexcitable, with greater numbers of spontaneous and evoked ac@on poten@als, increased expression of genes related to depolariza@on and reduced thresholds for ac@on poten@al genera@on. SUMMARY BPD, MDD and SZ may not be completely separate entities, sharing genetic risk alleles. ♦ DISC1 and CACNA1c are susceptibility genes for BPD and SZ. ♦ Most of the genetic risk for BPD and SZ remains unexplained. ♦ The identified rare and common DNA variants explain some of the genetic risk. ♦ Risk genes, in general, will not be specific to a given diagnostic category, and our current definitions of these illnesses must be ♦ re-written.