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No post-genetics era in human disease research

Abstract

In the 1980s, linkage emerged as a route to discovering genetic defects, spurring the rise of genomics and making gene-based approaches available to previously phenotype-orientated researchers. In the post-genomics era, genetics is fundamental to understanding disease at all stages of the pathogenic process.

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Figure 1: Genotypic and phenotypic approaches to the pathogenic process.
Figure 2: Potential model systems for investigating human disease mechanisms.
Figure 3: Genotype–phenotype correlations in Huntington disease patients.

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Acknowledgements

The author's work on HD is supported by the Huntington's Disease Society of America's Coalition for the Cure, the Hereditary Disease Foundation and by the National Institutes of Health.

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Correspondence to James Gusella.

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DATABASES

LocusLink 

apolipoprotein E

APP

Col1a1

Dmd

GRIK2

HD

Hdh

LDLR

merlin

MYH9

Nf2

presenilin 1

presenilin 2

TNSALP 

OMIM 

Alzheimer disease

ataxia-telangiectasia

dentatorubropallidoluysian atrophy

Duchenne muscular dystrophy

familial hypercholesterolaemia

Huntington disease

hyperkalaemic periodic paralysis

hyperthermia

hypokalaemic periodic paralysis

hypophosphatasia

long QT syndrome

macrothrombocytopaenia syndromes

myotonia congenita

neurofibromatosis 2

osteogenesis imperfecta

paramyotonia congenita

ryanodine receptor

SCA1

SCA2

SCA3

SCA6

SCA7

spinal and bulbar muscular atrophy

Glossary

AMYLOID PLAQUE

Specific structures made up of insoluble, relatively inert fibres of protein in β-sheet conformation.

BASAL GANGLIA

Clusters of neurons located deep in the brain that relay messages between the most anterior part of the cortex that is involved in problem solving and complex thought, and the lower motor and sensory areas; includes the striatum.

CAUDATE NUCLEUS

Part of the basal ganglia that bulges into the lateral ventricle and forms part of the striatum.

CEREBRAL CORTEX

Superficial layer of grey matter that is involved in higher functions, including initiation of voluntary movements, cognition and emotion.

CHOREA

Ceaseless, involuntary, jerking movements of the body, face, or extremities.

CONFORMER

One form of a protein that can exist in different conformations.

EXCITOTOXICITY

Toxicity to electrically excitable cells due to excessive electrical stimulation.

GABAERGIC PROJECTION NEURON

A neuron that uses γ-aminobutyric acid (GABA), a principal neurotransmitter, and sends axons to other brain regions.

NEUROFIBRILLARY TANGLE

Abnormal intracellular accumulation of a microtubule-associated protein called tau, characteristic of Alzheimer disease.

REACTIVE GLIOSIS

Appearance of activated glial cells in regions of brain injury.

STRIATAL NEURONS

Neurons that lie in the striatum — an area of the brain involved in fine movements, emotion and cognition.

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Gusella, J., MacDonald, M. No post-genetics era in human disease research. Nat Rev Genet 3, 72–79 (2002). https://doi.org/10.1038/nrg706

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