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2016 ; 12
(4
): e1005852
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The Increasing Importance of Gene-Based Analyses
#MMPMID27055023
Cirulli ET
PLoS Genet
2016[Apr]; 12
(4
): e1005852
PMID27055023
show ga
In recent years, genome and exome sequencing studies have implicated a plethora
of new disease genes with rare causal variants. Here, I review 150 exome
sequencing studies that claim to have discovered that a disease can be caused by
different rare variants in the same gene, and I determine whether their methods
followed the current best-practice guidelines in the interpretation of their
data. Specifically, I assess whether studies appropriately assess controls for
rare variants throughout the entire gene or implicated region as opposed to only
investigating the specific rare variants identified in the cases, and I assess
whether studies present sufficient co-segregation data for statistically
significant linkage. I find that the proportion of studies performing gene-based
analyses has increased with time, but that even in 2015 fewer than 40% of the
reviewed studies used this method, and only 10% presented statistically
significant co-segregation data. Furthermore, I find that the genes reported in
these papers are explaining a decreasing proportion of cases as the field moves
past most of the low-hanging fruit, with 50% of the genes from studies in 2014
and 2015 having variants in fewer than 5% of cases. As more studies focus on
genes explaining relatively few cases, the importance of performing appropriate
gene-based analyses is increasing. It is becoming increasingly important for
journal editors and reviewers to require stringent gene-based evidence to avoid
an avalanche of misleading disease gene discovery papers.
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