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Familial factors in human diseases 3 unfamiliar FAMILIAL research windows Juha E Jääskeläinen MD PhD Professor / UEF Neurosurgery Chairman / Neurosurgery / KUH NeuroCenter [email protected] SINCE 2010 Exomes only 1.5% – what is 98.5% of the genome doing ? SINGLE human cell contains amazing amount of information human brain CONNECTOME from one fertilized egg – 1.000.000.000.000.000 (1015) synapses – human brain equals the combined computer capacity of the world ! – where are BLUE PRINTS of the human brain connectome ? human cell is able to self-replicate – the only self-replicating machine in the known universe – so far Insects with a small number of cells are capable of amazing performances – how ? how can a fly fly accurately ? – only 100.000 neurons – but 10.000.000 synapses how can ants build a social megasociety ? – 18.000 genes – 23.000 in human cells – only 250.000 neurons – only 20.000.000 cells • all cells learn – not only neurons ? • cells have working memory and hard disk memory ? – a colony of 40,000 ants has the size of human brain 1. BENIGN CNS tumors and rare inherited tumor suppressor gene diseases – unique research window to early tumorigenesis 2. Placenta is most understudied life supporting organ – genomic and epigenomic marks in fetal tissues that affect life and disease after birth 3. Familial forms of complex neurodiseases – creation of population-based disease cohorts in 3 to 5 pedigrees with data fusion from national clinical databases BENIGN CNS tumors in SPORADIC patients • • • • • • single / well-demarcated / grow slowly WHO grade I (II) in I to IV histological scale curable by microscopic removal rarely turn malignant / do not metastasize tumor cells may show inactivation of specific tumor supressor gene • NF1 NF2 VHL TSC et al few other genomic aberrancies BENIGN CNS tumors and rare inherited tumor suppressor gene diseases – Knudson two-hit hypothesis all cells in disease carrier all cells in sporadic patient NF1 neurofibromatosis type 1 all cells contain one affected allele of NF1 gene on chromosome 17 1 : 3.500 newborn pilocytic astrocytomas – why ? multiple neurofibromas – why ? may turn malignant NF2 neurofibromatosis type 2 all cells contain one affected allele of NF2 gene on chromosome 22 1 : 35.000 newborn bilateral schwannomas of vestibular nerve (hallmark) – why ? multiple schwannomas – why ? multiple meningiomas – why ? NF2 neurofibromatosis type 2 all cells contain one affected allele of NF2 gene on chromosome 22 1 : 35.000 newborn bilateral schwannomas of vestibular nerve (hallmark) – why ? multiple schwannomas – why ? multiple meningiomas – why ? ezrin-merlin NF2 and Ezrin-Merlin Study Group from genes to tumours HU Pathology and Virology 1993 – 2000 1. BENIGN CNS tumors and rare inherited tumor suppressor gene diseases – unique research window to early tumorigenesis 2. Placenta is most understudied life supporting organ – genomic and epigenomic marks in fetal tissues that affect life and disease after birth 3. Familial forms of complex neurodiseases – creation of population-based disease cohorts in 3 to 5 pedigrees with data fusion from national clinic registries Can relevant predisposing data still be squeezed from DNA of peripheral blood leukocytes (blood samples) ? neurosurgeon neurologist cardiac surgeon cardiologist gastrosurgeon gastroenterologist orthopedist physiatrist urologist nephrologist pediatric surgeon pediatrician plastic surgeon dermatologist EPIGENOMIC profiling of tissues and organs during fetal period (Barker hypothesis) and during later life predispose to many COMPLEX diseases Many DISEASES are COMPLEX – affected by epigenomic / genomic / acquired risk factors – many also cluster in families and pedigrees embryonal phase fetal phase – epigenomics of complex diseases placenta – most understudied life supporting organ ! risk factors in population familial disease forms concomitant diseases pre-diagnosis features phenotype at diagnosis therapeutic approaches complications of therapies inflammation gut microbiome longterm outcome and morbidities causes of death Information Technology Mathematics Computer Science Biostatistics Programming Logistics Proactive Preventive Personalized Familial Care Clinical Bioinformaticians + Biobanks Disease Databases with data from National Registries Genomics Glycomics Epigenomics Pharmacogenomics Transcriptomics Cell / Tissue Biology Proteomics Anatomy Physiology Signalomics Disease Biology Metabolomics Disease Bioinformatics Kuopio NPH Patient and Brain Biopsy Tissue Bank Early Alzheimer’s Disease Group www.uef.fi/nph PI Docent Ville Leinonen >800 subcortical brain biopsies of NPH patients research aim • molecular biology of early Alzheimer’s disease final aims • use brain biopsies to verify AD at early phase ? • support trials of early preventive drug therapies 25 original articles Helsinki Saccular Intracranial Aneurysm (sIA) Wall Biobank Docent Juhana Frösen – molecular biology sIA wall Helsinki Biomedicum since 2001 – – Juhana Frösen / Mika Niemelä / JEJ Resection of sIA dome after clipping of neck – Juha Hernesniemi – microsurgery – somes snap frozen at OR – >700 sIA domes – sporadic or familial Molecular biology – unruptured vs ruptured human sIA wall – experimental rodent aneurysm model – 6 PhD Theses Kuopio sIA Patient and Family Database www.uef.fi/ns Kuopio sIA Patient Database 1980 – – 4.300 sIA patients + germline DNA archive • 25.000 relatives in 3-5 generations – 13.000 matched (3 to 1) Eastern Finnish controls – diseases / drugs / deaths from national registries – aim – phenotype / genomics / outcome of sIA-SAH – aim – biology of formation / growth / rupture of sIA Kuopio sIA Family Database – 300 sIA families + 41.000 relatives – 2 genealogists – multigenerational medapedigrees – to find rare causative (LoF) variants 10 PhD Theses Aarno Palotie Mitja Kurki PhD Mikael von und zu Fraunberg Broad Institute PI of SISU Project exomes of 200.000 Finns Bioinformatician of KUH Neurosurgery 2011– Post Doc 2014– Broad Institute Associate Chief Neurosurgeon PhD (porphyria genetics) MSc Engineer (computer sci) Master of Laws MSc Economics 1618 Finnish sIA patients + 2.513 controls 717 Dutch sIA patients + 3.004 controls loci on 2q23.3 – 2q33.1 – 5q31.1 – 6q24.2 – 7p22.1 – 9p21.3 explain only > 3 % of sIA heritability in Finland ! ’missing heritability’ in huge cohorts of COMPLEX DISEASES T2D HT AD … shift to deeply pedigreed and phenotyped DISEASE FAMILIES ? increased clinical penetrance inbreeding (consanguinity) Familial sIA disease – thorough phenotyping Sequencing to identify predisposing genomic variants ? sIA x sIA marriage risk 0.9 / 1.000 = 3/100 x 3/100 5 pedigrees in Kuopio sIA Database Antti Lindgren Antti Ronkainen Kuopio sIA Database Familial sIA disease – deep pedigree Accuracy of sIA diagnosis (+/-) vs calendar years calendar years 1800 1900 CT 80 MRI 93 2014 Familial sIA disease in Eastern Finland – inbreeding construction of multigenerational sIA megapedigrees I I:1 I:2 II II:1 III III:1 IV III:2 IV:1 V VI:3 IV:2 VI:3 VI:3 VI:4 V:1 VI VI:1 VII VII:7 VIII IX:10 IX X IX:9 X:12 X:11 XIII XIII:7 VII:6 IX:8 IX:10 X:10 XI:9 XII:9 VII:5 IX:11 IX:8 XI XII VII:8 XI:8 IX:9 IX:11 X:9 XI:6 X:8 XI:7 XII:8 XII:12 XII:11 XII:16 XII:15 XIII:8 XIII:9 XIII:10 XIII:11 XIII:12 VIII:8 XII:18 XII:17 XII:10 X:5 XII:14 XII:19 VIII:3 VIII:4 IX:6 IX:3 X:3 XI:3 XII:13 VIII:6 IX:5 X:6 XI:4 VII:2 VIII:5 IX:7 X:7 VI:2 VII:1 VIII:7 V:2 XII:20 X:4 XI:5 XI:1 XII:21 XII:22 XI Information Technology Mathematics Computer Science Biostatistics Programming Logistics Proactive Preventive Personalized Familial Care Clinical Bioinformaticians + Biobanks Disease Databases with data from National Registries Genomics Glycomics Epigenomics Pharmacogenomics Transcriptomics Cell / Tissue Biology Proteomics Anatomy Physiology Signalomics Disease Biology Metabolomics Disease Bioinformatics Juha E Jääskeläinen – browsable data in future Biodatabank of Pedigreed Eastern Finnish Population grandfather – died of AD grandmother died of T2D (insulin) Would you– ? father (nomarry DNA) –me died at 73 of sIA-SAH • drug-treated have T2D children with me • heavy employ smoker / me no hypertension mother (refused biobanking) sell lifeDNA insurance to me almost blind at 84 due to macular degeneration Juha E Jääskeläinen (exome sequencing) • SISu Project (exomes of 200.000 Finns) – heterozygote for 10 rare alleles of lethal diseases – carrier of rare loss-of-function (LoF) variants • n of NNN AD variants • n of NNN T2D variants • n of NNN hypertension variants • n of NN sIA variants 1. BENIGN CNS tumors and rare inherited tumor suppressor gene diseases – unique research window to early tumorigenesis 2. Placenta is most understudied life-supporting organ – genomic and epigenomic marks in fetal tissues that affect life and disease after birth 3. Familial forms of complex neurodiseases – creation of population-based disease cohorts in 3 to 5 pedigrees with data fusion from national clinical databases VHL von Hippel-Lindau disease all cells contain one affected allele of VHL gene on chromosome 22 1 : 35.000 multiple hemangioblastomas – why ? bilateral renal cell carcinomas – why ?
