Microarray vs. Whole Genome Sequencing: The Differences
Two main methods stand out in genetic testing: microarray (SNP chip) and whole genome sequencing (WGS). Both read DNA, but what they read, where they are reliable and which questions they can answer differ. In this article we explain these differences, and the statistical method called imputation, in plain language.
What does a microarray read?
A microarray is a chip carrying probes that bind to predetermined DNA sequences. It reads which letter you carry at hundreds of thousands of known variant points in the genome. The points it reads are chosen when the chip is designed. The chip does not read regions outside these points.
The strength of the microarray is that it reads common variants with very high accuracy. In a large study comparing both chip and sequencing data from about 50,000 people, sensitivity, specificity and positive and negative predictive values were all above 99% for 108,000 common variants read directly on the chip.
What does whole genome sequencing read?
Whole genome sequencing aims to read most of the roughly 3 billion letters of DNA. This means it can also capture previously unknown or very rare variants. This breadth comes at a cost: more data, more analysis and more interpretation are needed. The likelihood of encountering variants whose clinical significance is not yet known (variants of uncertain significance) also increases.
Comparison
| Microarray (SNP chip) | Whole genome sequencing | |
|---|---|---|
| What does it read? | Pre-selected variant points | Most of the genome |
| Accuracy for common variants | Very high | Very high |
| Very rare variants | Not reliable, confirmation needed | Can be read; clinical use still requires expert interpretation |
| New (unknown) variants | Not read | Can be read |
| Suitable questions | Tendencies associated with common variants, ancestry analysis | Rare disease investigation, comprehensive clinical assessment |
What is imputation?
Imputation is the statistical estimation of variants not read directly on the chip, using the variants that were read and a reference panel made up of thousands of previously sequenced genomes. Because variants located close together are usually inherited together, this estimate gives reliable results for many variants. The method is widely used in genome-wide association studies.
Imputation has limits worth knowing:
- An estimate is not a measurement. A confidence score is calculated for every imputed variant. Variants with a low score are less reliable.
- Accuracy depends on many factors. Chief among them are how common the variant is in the population and how well the reference panel represents the person's population. Rare variants are harder to estimate.
- It is not sufficient for clinical decisions. A finding that may be clinically important should rest on direct measurement and a confirmation test, not on an estimate.
Why is caution needed with rare variants?
The same large study showed that the reliability of chip results drops sharply as variants become rarer. For variants seen in fewer than 1 in 100,000 people, only 16% of the 4,757 heterozygous genotypes found by the chip could be confirmed by sequencing. For rare pathogenic variants in the BRCA1 and BRCA2 genes, the chip's positive predictive value was 4.2%. In other words, only about 4 of every 100 positive results on the chip were truly positive. The researchers concluded that SNP chips are extremely unreliable for detecting very rare pathogenic variants and should not be used as the basis for health decisions without confirmation.
In another study, in which variants reported in the raw data of consumer tests were retested in a clinical laboratory, 40% of these variants turned out to be false positives.
Which method is right for you?
- For questions based on common variants, such as training, nutrition, skin care and ancestry, microarray is a suitable and widely used method.
- If your family has a history of early-onset cancer, an unexplained heart condition or a disease thought to be hereditary, the answer to that question lies not in a consumer test but in clinical genetic testing with a doctor and a genetic counselor.
Hub Genetik tests use the microarray method, and the report is limited to selected variants with scientific evidence. Details of the method are on the Science & Safety page, and the structure of the report is shown in the sample report. In the GEN's UP Package, which includes selected cancer predisposition and drug response variants, these sections are not clinical screening or diagnostic tests. Findings in these sections require a confirmation test and a doctor's assessment.
References
- Weedon MN, Jackson L, Harrison JW, et al. Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation. BMJ. 2021;372:n214. PMID: 33589468. doi:10.1136/bmj.n214
- Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet. 2010;11(7):499-511. PMID: 20517342. doi:10.1038/nrg2796
- Das S, Forer L, Schönherr S, et al. Next-generation genotype imputation service and methods. Nat Genet. 2016;48(10):1284-1287. PMID: 27571263. doi:10.1038/ng.3656
- Tandy-Connor S, Guiltinan J, Krempely K, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 2018;20(12):1515-1521. PMID: 29565420. doi:10.1038/gim.2018.38