Dear Dr Hamdan Zaki Hamdan,

allow me to reproduce this text to remind possible reasons for HWE departure

( Cathryn M. Lewis and Jo Knight - I ntroduction to Genetic Association Studies - Cold Spring Harbor Protoc; 2012; doi:10.1101/pdb.top068163 )

"Departures from HWE in control samples may be caused by the following:

Genotyping error. In many genotyping platforms, calling heterozygotic individuals is more challenging than homozygotic individuals, and a higher rate of missing individuals for this genotype can distort HWE.

Assortative mating. HWE requires random mating for the SNP under test, which is reasonable for a random SNP across the genome, but may be violated for SNPs that affect mate choice, such as height.

Selection. Any genotype increasing the risk of fetal loss or early death is likely to be under- represented.

Population stratification. Control samples that arise from a combination of genetically distinct subpopulations may not be in HWE.

Chance. HWE p values for studies of more than one SNP should be corrected appropriately for multiple testing. "

You must to check consistently each of the listed reasons and then you will know the exact cause of HWE deviation.

Best wishes,

Vladimir Pushkarev

Well it depends:

Genotyping error: For some genotyping methods - those that somehow provide a possibility to obtain a so called cluster plot (mostly high throughput methods), you could have a look at that.

Stratification: With genome wide data one could carry out a PCA and detect stratification in the assessed sample.

These to are the most common reasons, so I'd look for these first

I agree with the explanation given by Vladimir and Josef. Please also see attached article hope it will help you to further understand the deviation from HWE

Is this in a controlled (lab) or uncontrolled (nature) setting? If the latter, the possible explanations are numerous. The answers above are correct when stating genotyping error can be a major case of deviation from HWE, but this can be explicitly tested and is relatively easy to determine. Mutation and selection are two other possibilities given they both are at play in most naturally occurring populations. The former is very difficult to evaluate in natural populations, but other genetics parameters (changes in heterozygosity and/or linkage disequilbrium) and the process of deduction can at minimum allude to a yes/no answer for selection. Immigration and resulting admixture can also cause HWE deviations at specific loci, and tests are available for evaluating this. 

In a controlled setting, these things are much easier to investigate. Something to consider is that most naturally occurring populations don't conform to the HWE assumptions, and - perhaps more importantly - genetic drift is always an acting and opposing force to selection, etc. in these populations.

I agree with all the given answers, especially I liked the answer of Dr. Pushkarov

I agree with Sean; you should consider whether it is in a lab or natural setting.  Genetic drift, mutation and selection are all possible reasons in the natural world and should be explored.

 In continuation with Dr. Valdmir Pushkarev,,therefore, to test a particular cause or causes, there are specific formulas and associated statistical tests available. It is also necessary one should get information about population structure, history of settlement, marriage patterns and other relevant information. Mere getting a genotype data and HW test will tell you to look for the specific factors that influence the observed data. Instead with the above information, even it is possible one can even frame a working hypothesis invoking a particular cause and test it with the appropriate tools. Therefore, a detailed and careful information about the population is important. 

I also agree with Sean.

For identification of population stratification to analyse check if the HWE deviation is due to admixture sample you can use "structure". It is free and easy to use

Thank you very much Asia, Vladimir,Josef, Vaslu,  Angela, Sean for your contribution and enriching the debate. Your answer was helpful.  

HWE has many requirements including systematic factors ( mutation , migration , selection ) and dispersive factors ( genetic drift ) , these factors did not work separately but all work in the same time and the opposite of mutation and selection need to reach balance between them .

Natural population may be difficult to have all requirements especially large population and random mating .

Good Luck

Thank you Dear Khalid for your reply

Please get in touch with some published books on "population genetics". There you get know the methods to follow to test different factors that might be responsible for deviation from HW equilibrium. You can also get these from online resources. There are good notes and methods to test for it. This possibly requires, a knowledge of statistics to work out. Please also check publications in various journals -- both on the data of classical genetic markers and molecular genetic markers as well. You can refer our publications as well. e.g., genetic consequences of demographic upheavals in Adi Pasi tribe in India. There are publications of DR Roberts on genetic drift, a lot good publications on a variety of selection types among different populations -- man and animals.  

Much appreciated Dear Vasulu