Using data from a set of twins, one with Down's and one without, researchers found a major difference in how genes functioned between the two.
The twins were born from a single egg that split, which means their DNA code started off identical.
Read: 10 Down syndrome facts
But the individual with Down's had an extra copy of Chromosome 21 – a difference enabling the scientists to see how this might affect the same genome.
The additional chromosome had a knock-on effect on all the 22 other chromosomes, the team reported in the journal Nature.
"We were very surprised by this finding," said Audrey Letourneau of the University of Geneva Medical School who co-authored the study.
"It seems that this small, extra chromosome has a major influence on the entirety of the genome."
Chromosomes are made up of bundles of DNA called genes, which hold the information for cell function.
Humans have 23 pairs of chromosomes – or a total of 46 per cell.
Genetically caused mental disease
People with Down's Syndrome, about one in every 750, have a third, extra Chromosome 21 – the smallest of all the chromosomes with about1% of the DNA in a cell.
Down's is the world's leading genetically-caused mental disease, and also carries a heightened risk of heart defects, leukaemia, immune-system malfunction and premature Alzheimer's disease.
The results may help researchers "find substances that could reverse this gene-expression dysregulation, i.e. drugs that revert the expression of genes... back to normal," co-author Stylianos Antonarakis told AFP.