Medical conditions and risk factors associated with mtDNA haplogroups

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Genetic diseases are obviously caused by our genes. The progress in the field of genetics is constantly giving us new clues regarding the correlations between certain genetic types and a risk to develop some diseases.

Mitochondrial DNA (mtDNA) only represents a tiny fraction of a person's DNA. However, it plays an important role in the energy production within cells, and are hence referred to as the "powerhouses" of the cell. About 2 billion mitochondria are made every second throughout a person’s life, each having an average life of around 100 days.

MtDNA is exclusively inherited through the mother, and remains unchanged for many generations. Mutations occur randomly after anything between 10 and 50 generations. This makes it possible to classify human beings into haplogroups sharing a same number of mutations. Each individual thus belongs to a definite mtDNA haplogroup. Haplogroups can be further divided into more precise subclades, sharing more mutations and therefore a more recent common ancestor than with the whole haplogroup.

MtDNA subclades are mostly determined by mutations in the coding region of the DNA (i.e. having medical functions). Consequently, it is possible that one or several mutations found in a particular haplogroup or subclade have a positive or negative effect on health. For instance, one's haplogroup can influence cancer risk either protectively or detrimentally (see examples below).

The following website has a list of mtDNA mutations associated with diseases :

- Coding & Control Region Mutations
- rRNA/tRNA Mutations

These mutations are not revealed by the common HVR1 and HVR2 tests for genealogical purposes, but require to test the full mtDNA sequence.

Mitochondrial diseases are most often associated with energy-related conditions, such as myopathy (neuromuscular disease, leading to muscle paralysis) and cardiomyopathy (heart muscle disease), single nerve paralysis (notably the optical nerve), exercise intolerance, but also more benign symptoms like fatigue, overall weakness, headaches, or loss of appetite.

Other medical conditions related to mtDNA include osteoporosis, Alzheimer's disease, Parkinsons's disease, etc.

Examples of diseases associated with a haplogroup

Among European populations

The risks of developing Parkinson Disease have been found to be higher among mtDNA haplogroups H, but lower for haplogroups J and K.

Men belonging to haplogroup H have the lowest risk of asthenozoospermia (reduced sperm motility), while those of hpg T have the highest.

There is a correlation between haplogroup H and protection from sepsis.

Haplogroups I, J1c, J2, K1a, U4, U5a1 and T have lower incidences of Parkison's Disease. I, J and T also have increased longevity. However, haplogroups J and T have been associated with increased risk for expression of a maternally inherited blindness disorder (Leber hereditary optic neuropathy). This is especially true for the J2 subclade.

Haplogroup T is associated with coronary heart disease, but also a decreased risk of diabetes (source 1, source 2, source 3).

Haplogroup N is considered a risk factor for breast cancer. This also applies to all its sub-haplogroups (H, T, U, V, W, X) except for hpg K.

Mitochondrial haplogroup U is associated with an approximately 2-fold increased risk of prostate cancer and renal cancer.

Coskun et al. says that haplogroups J and UK are protective against Alzheimer's disease (AD), whereas haplogroup H is thought to increase the penetrance of AD. One of the mutations found in AD patient but not in controls was T414G.

Haplogroup U and its subclade K are associated with higher risks of strokes and Chronic Progressive External Ophthalmoplegia.

Haplogroup X has a defining mutation related to type-2 diabetes, cardiomyopathy and endometrial cancer risk.

Studies have suggested haplogroup IWX to be highly protective against AIDS progression.

Among East Asian populations

Longevity is associated with haplogroup D4a.

Haplogroups D4a and D5a are associated with higher risk of esophageal cancer.

Haplogroups F and A are genetic risk factors for diabetes, whereas haplogroup N9a was found to be a protective factor against Metabolic syndrome (cause of cardiovascular disease and diabetes), especially for women.

Haplogroup M7b2 was found to be a genetic risk factor for leukemia.

People belonging to haplogroups B4c, G1 and H4 are more predisposed to obesity.

Members of haplogroup G (found in North-East Siberia) have increased risks of Non-Insulin Dependent Diabetes Mellitus.

Such studies are still in their infancy. The years, and indeed decades to come will shed more light on the relation between diseases and genes. What is more, the results of these studies are not easily accessible to the general public, or are often too technical to be easily understood for lay people. But if you find some interesting data, feel free to post it here as a summary of the information jungle in which we live.

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Two of the most common pathogenic mitochondrial mutations are A3243G and T14484C. (sources). The former is responsible for Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes, and the latter for Leber Hereditary Optic Neuropathy.

Both are found in specific subclades of haplogroup J or independently in various haplogroups, notably H and T.

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A new study contradicts the claim that haplogroup J is associated with centenarians. Among Ashkenazi Jews, there does not seem to be a significant difference between mtDNA haplogroups in centenarians and in the control group.

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A new article on Dienekes' Blog mentions that AIDS progression is faster amongst haplogroups J and U5a, but slower for members of haplogroups UK, H3, and IWX. UK supposedly means all subclades of U and K, and IWX means hg I, W and X. This is contradictory though since U5a is associated with faster progression.

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Mitochondrial DNA is a cause of acute intermittent porphyria. The disease has been linked with mtDNA 14484 mutation found in Dutch members of haplogroups J and K.

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Mitochondrial Variants in Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

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Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA) sequence have been reported in SZ and BD patients.

This study examines the association between brain pH and mtDNA alleles. The stronger association (highest pH) was found for haplogroups U and K. The A10398G polymorphism (defining hg I, J and K1) was found to be associated with an increased pH in cybrid cells.

Higher pH confers a protective effect of the haplogroup U, K, J and T against Parkinson's disease and psychiatric disorders.

Other studies suggested that a lower brain acidity (i.e. higher pH) has a protective effect against strokes.

Research on intelligence point that people with higher IQ tend to have more alkaline brains. Higher pH is associated with better conductivity-transmission between neurons (source).

On the other hand, the study found a tendency towards association of psychiatric disorders with H haplogroups (meaning lower pH).

The most significant mutation associated with schizophrenia and depression is T10652C, found primarily in haplogroups pre-HV, N1b1 and D1. Three other mutations were typically present along with T10652C in affected individuals : T14783C, G15043A, and T9540C.

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Haplogroup H is strongly associated with increased lipoatrophy following a antiretroviral therapy, while haplogroup T is somewhat protective.

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According to Petros et al. mtdna mutation T8993T is associated with a 7-fold increased risk for prostate cancer. This mutation does not define any haplogroup or common subclade.

Coskun et al. found the C150T mutation to be associated with centenarians and resistance to stress. C150T is found in various haplogroups. The study found cases in the European haplogroups N1b, HV, H, J, T and U.

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A new Spanish study found that haplogroup H was associated with a higher oxygen uptake compared to average. Haplogroup J, on the other hand, had the opposite association.