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  • Review Article
  • Published:

Neuropeptide gene polymorphisms and human behavioural disorders

Key Points

  • A single-nucleotide polymorphism (SNP) is a specific location in a genome at which different individuals have different DNA bases, which can, for example, result in changes in the sequence of an encoded protein.

  • A small number of SNPs are associated with disease inheritance, and their characterization could be valuable in understanding the disease pathophysiology.

  • This review discusses SNPs in genes encoding neuropeptides and neuropeptide receptors that underlie complex disease states.

  • The main focus is the role of neuropeptides in feeding behaviour and body-weight regulation, as this is the area in which most drug discovery efforts are directed at present, although the roles of neuropeptides in other behaviours are also discussed where appropriate.

Abstract

Energy homeostasis is controlled by a complex neuroendocrine system consisting of peripheral signals, such as leptin, and central signals, particularly neuropeptides. Animal experiments have demonstrated that neuropeptides present in the hypothalamus and other brain areas are important not only in the regulation of feeding and metabolism, but also in other neuroendocrine and behavioural functions. Knowledge about neuropeptides is increasingly used in the study of the pathophysiology of behavioural disorders. This review focuses on the influence of polymorphisms in genes encoding neuropeptides or neuropeptide receptors involved in diverse physiological processes. The identification of neuropeptide systems closely associated with human illnesses will aid the development of novel therapeutic strategies.

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Figure 1: Influences of a neuropeptide Y polymorphism.
Figure 2: POMC deficiency syndrome.
Figure 3: Phenotypic differences in humans and mice with leptin deficiency.
Figure 4: MC-4 receptor mutations and human obesity.
Figure 5: CCK-related polymorphisms and human diseases.

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Acknowledgements

I sincerely thank M. Kasuga and S. Baba of Kobe University for stimulating discussions. The work was supported by grants from the Japanese Ministry of Education, Science, Sports, and Culture.

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DATABASES

LocusLink

AgRP

CART

CCK

CCK1 receptor

CCK2 receptor

CRF

ghrelin

growth hormone secretagogue receptor

MC-1R

MC-2R

MC-3R

MC-4R

MC-5R

MCH

neuromedin B

NPY

NPY Y1

NPY Y5

orexin 2 receptor

POMC

prepro-orexin

FURTHER INFORMATION

Online Mendelian Inheritance in Man

Rheumatoid arthritis

Parkinson's disease

Glossary

ASSOCIATION STUDY

In genetics, the word 'association' refers to the occurrence together of two or more characteristics more often than would be expected by chance alone.

LINKAGE DISEQUILIBRIUM

Association is to be distinguished from linkage, which is the tendency for certain genes to be inherited together because they are on the same chromosome. Linkage disequilibrium indicates that the two alleles are physically close on the same DNA strand.

HYPOTHALAMUS

A basal part of the diencephalon that lies beneath the thalamus on each side, which includes vital regulatory centres, for example, for the control of food intake.

NARCOLEPSY

A sleep disorder that usually presents in young adulthood, consisting of recurring episodes of sleep during the day and often disrupted nocturnal sleep. Narcolepsy affects more than 100,000 people in the United States alone, and seems to have a genetic basis. Treatment often includes the use of amphetamines and/or tricyclic antidepressants.

PENETRANCE

The likelihood that a given gene will result in disease. For an autosomal-dominant disorder, if only a proportion of individuals carrying the mutant allele display the abnormal phenotype, the trait is said to show incomplete penetrance. If all with the mutant allele show the abnormal phenotype, the trait is said to have complete or full penetrance.

AGANGLIONIC MEGACOLON

A birth defect of the bowel in which there is an absence of the ganglia (nerves) in the wall of the bowel. Nerves are missing starting at the anus and extending a variable distance up the bowel. This results in megacolon (massive enlargement of the bowel) above the point where the nerves are missing. Also called Hirschsprung's disease.

PLEIOTROPY

The phenomenon in which a single gene is responsible for several distinct and seemingly unrelated phenotypic effects.

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Inui, A. Neuropeptide gene polymorphisms and human behavioural disorders. Nat Rev Drug Discov 2, 986–998 (2003). https://doi.org/10.1038/nrd1252

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