Basi genetiche e meccanismi alla base di condizioni di interesse

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Basi genetiche e
meccanismi alla base
di condizioni di
interesse biomedico
Genetics is the science of genes, heredity and variation in
living organisms
In simple mendelian traits, the relationship between the causal
genetic variant (genotype) and the disease state is deterministic.
In a complex trait, the disease state results from interactions
between multiple genotypes and the environment. The influence
of any individual causal allele tends to be modest and the
relationship between the causal variant and the disease state is
probabilistic.
Qualitative trait
Quantitative trait
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Why Sardinia?
Why a sequencing project in Sardinia?
CROATIA
UKRAINE
SARDINIA
HUNGARY
POLAND
CATALONIA
BASQUE COUNTRY
GEORGIA
ANDALUSIA
CORSICA
SICILY
NORTH-CENTRAL
ITALY
ALBANIA
GREECE
LEBANON
CALABRIA
TURKEY
ITALY
LANUSEI CAGLIARI
CARBONIA
TEMPIO
ORISTANO
SASSARI
SORGONO
1 Cagliari
2 Carbonia
3 Lanusei
4 Oristano
5 Sassari
6 Sorgono
7 Tempio
Lampis et al Human Molecular Genetics. 2000, 9, 2959-2965
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By courtesy of G.
Manca
By courtesy of G.
Manca
• What Traits we have been studying
in Sardinia?
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•  ProgeNIA study (quantitative traits)
•  Case-Control studies (qualitative traits)
ProgeNIA
6.148 volontari
Arzana
Elini
Ilbono
Lanusei
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Giuseppe Pilia, Ideatore e Fondatore del Progetto ProgeNIA
ProgeNIA/SardiNIA project
 6,148 individuals - aged 14-102 y.
95% are known to have all grandparents born in Sardinia
 711 pedigrees up to 5 generations deep
Largest family: 625 phenotyped individuals
 >34,000 relatives pairs
Pilia et al. PLoS Genet. 2006
> 120 quantitative traits
  Anthropometric
Measurements
Height, Weight, Hip, Waist, BMI
 Blood Chemistry Components
LDL, HDL, TG, Insulin, RBC, MCH, MCV, Bilirubin, hsCRP, MCP-1,
IL-6, etc.
  Cardiovascular Traits
HR, SBP, DBP, PP, PWV, IMT, QT, etc
  Personality Facets
Neuroticism, Extraversion, Openess, Agreeableness,
Coscientiousness, etc.
  New traits will be added soon (immunological traits)
 Cytokines
Adiponectin, Leptin, MCP-1, hsCRP, IL-6, V-CAM, AGE
 Bone mineral density and physical tests
Six new loci associated with body mass
index highlight a neuronal influence on body
weight regulation. Nat Genet. 2009 Jan;41
(1):25-34
MAGIC: Meta-Analyses of Glucose and Insulin-related traits Consortium,
creato per identificare geni che influenzano la glicemia e tratti metabolici.
ProgeNIA, deCODE, Northern Finland Birth Cohort 1966 (NFBC1966),
Netherlands Twins Register/Netherlands Study of Depression Anxiety),
Rotterdam Study; Genetics of Energy Metabolism, CoLaus, TwinsUK scans,
British 1958 Birth Cohort, DGI, FUSION, Framingham Heart Study (FHS)
GIANT: Genome-wide Investigation of ANThropometric measures, creato per
lo studio dei tratti antropometrici. ProgeNIA, FUSION, EPIC, CoLaus,
WTCCC, DGI, PLCO, NHS, KORA, British 1958 Birth Cohort, Rotterdam,
InCHIANTI, BLSA.
QTSCD: QT and Sudden Cardiac Death consortium , creato con l’obiettivo di
identificare la componente genetica dell’intervallo QT. ProgeNIA, ARIC, HNR,
GenNOVA e KORA.
CFPWV: Carotid-Femoral Pulse Wave Velocity consortium, creato per
identificare la componente genetica della pulse wave velocity. ProgeNIA,
FHS, AGES, ERGO, GRIP.
MetaThyroid: creato per identificare le basi genetiche dei tratti che
regolano la funzionalita’ tiroidea. ProgeNIA, InCHIANTI, BLSA, MICRSO
(Sud Tirolo), IGV (Val Borbera e Friuli Venezia Giulia), Rotterdam, Old
Order Amish, twinsUK.
GlobalBPGEN: Genetic study of Blood-Pressure, creato per identificare la
componente genetica della pressione sanguigna. ProgeNIA, BLSA, British
1958 Birth Cohort, CoLaus, EPIC, InCHIANTI, KORA, NFBC1966,
Suvimax, TwinsUK, ProCARDIS, BRIGHT.
GWASNEO: creato per identificare le basi genetiche dei tratti che regolano
la personalità. ProgeNIA, NTR/NESDA, ERF , SAGE , HBCS , NAG,
QIMR, LBC36, BLSA.
CHARGE menarche and menopause: creato per identificare la
componente genetica dell’eta al menarca e alla menopausa. ProgeNIA,
AGES-Reykjavik, ARIC, B58C-T1DGC, B58C-WTCCC, CoLaus, deCODE,
DNBC, EGCUT, EPIC-obesity cases, EPIC-obesity cohort, ERF, FHS,
HAPI Heart Study, HBCS, Health 2000, InCHIANTI, Indiana, NHS-CGEMS,
NHS-HU, NFBC, NTR, QIMR, SAGE, TwinsUK , WGHS
CHARGE Fibrinogen: Genetic study of Blood-Pressure, creato per
identificare la componente genetica della pressione sanguigna. ProgeNIA,
FHS, RS, CHS, ARIC, KORA, B58C, WGHS, PROCARDIS, PROSPER/
PHASE, LBC1936, LBC1921, HBCS, VIS, ORCADES, CARDIA, SHIP,
InCHIANTI, NTR, GEMS, TwinsUK, MARTHA, MESA SHARe
CHARGE PR interval Consortium, creato per identificare la componente
genetica dell’intervallo PR. ProgeNIA, AGES, ARIC, CHS, FHS, KORA,
Rotterdam, tutti facenti parte del CHARGE consortium.
!
CHARGE RRGEN : creato per identificare la componente genetica dell’ RR.
ProgeNIA, AGES, ARIC, CHS, FHS, KORA, Rotterdam, tutti facenti parte
del CHARGE consortium.
HeamGEN: creato per identificare le basi genetiche dei tratti che regolano i
tratti ematologici. ProgeNIA, InCHIANTI, BLSA, MICRSO (Sud Tirolo), IGV
(Val Borbera e Friuli Venezia Giulia), Rotterdam, Old Order Amish, twinsUK,
ARIC, CHS, EPIC_cohort, HVH, INGICARL, INGIFVG INGIValBorbera,
KORAF3,
KORAF4,
LBC1921,
LBC1936,
LOLIPOP_EW_A
LOLIPOP_EW_P, MICROS, NTR, QIMR, SHIP, SORBS, TwinsUK,
NFBC66, POPGEN, UKBS
Lipids Consortium: creato per identificare la componente genetica della
concentrazione dei lipidi. ProgeNIA, FHS , the London Life Sciences
Prospective Population Cohort (LOLIPOP), Supple´mentation en Vitamines
et Mine´raux Antioxydants (SUVIMAX), InCHIANTI, DGI , FUSION.
SMOKGEN: creato per identificare la componente genetica della
dipendenza alla nicotina. ProgeNIA, GEMS, CoLaus, GSK COPD, GSK
UPD, GSK Bipolar, GK LOLIPOP, GSK Medstar, Penn-CATH, EPIC, KORA,
WTCCC HT, WTCCT, POPGEN, SHIP, VIP, ORCADES, KORCULA
Case-control studies in Sardinia
 
~2,500 healthy controls, recruited from all
over the Island from the main transfusion
blood centers
 
Cases from multifactorial autoimmune traits
collected from hospitals and University clinics.
Specifically:
  ~ 2,800 Multiple Sclerosis cases
  ~ 1,700 Type 1 Diabetes cases
  ~ 70 cases with both MS and T1D
Case-control samples
•  The special case of autoimmune diseases
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20 23
7
13
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26
10
8
6
22
13
13
7
10 15
8
9
10
6
9.8
12 8
8
6
42
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*Adapted from EURODIAB
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12
7
12
8
19
11
14
12
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36
9
7
7
5
6
9
18
15
8
5
119
165
74
120
153
186 187
135
93
56
55
35
112
126
76
55
86 83
50
55
47
39
62
83
50
112
81
65
55
140
10
21
42
6
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Pugliatti et al (EBC), Eur J Neurol 2006
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39
10
31
17
68
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theoretical framework
R. A. Fisher, 1890-1962
GWAS in ProgeNIA (~6000
individuals) in ~3K MS, ~2K
T1D and ~3K controls
Whole genome resequencing (2-4
x coverage) in a proper subset of
~3000 individuals
Inference and disease association testing
Comparison associations in
ProgeNIA e in T1D & MS and
check for shared associations
Validation top associations with an
independent assay
Meta-analysis with main consortia
Functional/biological studies
Experiment Timeline
GA IIx Start
Day 1
Illumina Pipeline
Day 10
BWA and Yun LI workflow
Day 13
Quality-Check Tools
Day 15
Timing for 115 Cycles Experiment on GA IIx
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How much computing?
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Infrastruttura
•  Cluster con potenza di calcolo di circa 47
TFlops
–  Cluster HP 34,6 TFlops
(bassa e media latenza)
–  Cluster Specializzati (Cell,
Tesla, GPU NVDIA)
–  Cluster IBM (Cybersar)
•  Storage (spazio disco) 1,2 PB
•  Backup 800TB
•  Infrastruttura di rete LAN con backbone
massimo di 80Gbps
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The International network
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David Schlessinger Chief, Human Genetics Section and Chief, Laboratory of Genetics of
National Institute of Aging
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Goncalo Abecasis, Professor of Biostatistics at Ann Arbor, University of Michigan, USA
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John Todd, Director, JDRF/WT Diabetes & Inflammation Laboratory, Cambridge
Institute for Medical Research, Univ. of Cambridge, UK
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Vincenzo Cerundolo, Director Human Immunology Unit,
Weatherall Institute of Molecular Medicine, University of Oxford, UK
ProgeNIA Team Lanusei-Cagliari
Manuela Uda
Serena Sanna
Eleonora Porcu
Ilenia Zara
Carlo Sidore
Maristella Steri
Marco Masala
Gianmauro Cuccuru
Angelo Scuteri
Marco Orrù
Maria Grazia Pilia
Danilo Fois
Liana Ferreli
Francesco Loi
Laura Crisponi
Silvia Naitza
Mariano Dei
Antonella Mulas
Maria Grazia Piras
Gianluca Usala
Andrea Maschio
Fabio Busonero
Sandra Lai
Edoardo Fiorillo
Valeria Orrù
Francesca Virdia
Monica Lai
Anna Cau
Barbara Deiana
Alessandra Cannas
Caterina Flore
Simona Foddi
Susanna Murino
Giuseppe Pilia, Ideatore e Fondatore del Progetto ProgeNIA
Acknowledgements:
Antonio Cao
Giuseppe Pilia
Paolo Zanella
Chris Jones
Roman Tirler
Mauro Congia
Sergio Uzzau
David Schlessinger
Goncalo Abecasis
John Todd